Phenyl carbamate compounds for use in preventing or treating epilesy

ABSTRACT

A method for treatment or prevention epilepsy comprising administering a phenyl carbamate compound in a pharmaceutically effective amount to a subject in need of treatment or prevention of epilepsy is provided.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to and the benefit of U.S. ProvisionalApplication No. 61/580,409, filed in the United States Patent andTrademark Office on Dec. 27, 2011, the entire contents of which areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a method for treatment or preventionepilepsy comprising administering a phenyl carbamate compound in apharmaceutically effective amount to a subject in need of treatment orprevention of epilepsy.

BACKGROUND ART

Epilepsy is a chronic neurological disorder presenting a wide spectrumof diseases that affects approximately 50 million people worldwide,which corresponds to 1% of the world's burden of disease, equalingbreast cancer in women and lung cancer in men. Epilepsy refers to aclinical phenomenon rather than a single disease entity, since there aremany forms and causes of epilepsy.

An essential step in the diagnosis and treatment of a patient with aseizure is to determine the type of seizure that has occurred. The maincharacteristic that distinguishes the different categories of seizure iswhether the seizure activity is partial or generalized.

On the basis of clinical and encephalographic phenomenon, foursubdivisions of epilepsy are recognized: grand mal epilepsy (withsubgroups: generalized, focal, jacksonian), petit mal epilepsy,psychomotor or temporal lobe epilepsy (with subgroups: psychomotorproper or tonic with adversive or torsion movements or masticatoryphenomenon, automatic with amnesia, or sensory with hallucinations ordream states) and autonomic or diencephalic epilepsy (with flushing,pallor, tachycardia, hypertension, perspiration or other visceralsymptoms).

Despite many trials to develop anti-epilepsy drugs, epilepsy is stillunmet in efficacies. Therefore, there is a need for improvedanti-epilepsy medications.

SUMMARY OF THE INVENTION

An embodiment provides an organic compound, i.e., phenyl carbamatecompound. More particularly, the embodiment is directed to a phenylcarbamate compound of the following Chemical Formula 1, an enantiomer ora diastereomer thereof, or a mixture of enantiomers or diastereomers; ora pharmaceutically acceptable salt of organic acid or inorganic acidthereof; which has remarkably excellent treatment effect on epilepsy aswell as very low toxicity. Also, the compounds of formula I may beuseful as a drug especially for the treatment of epilepsy:

wherein,

X is a halogen, for example, chlorine, fluorine, iodine, or bromine,

n, that means the number of substituent X, is an integer from 1 to 5,for example, 1 or 2,

R1 is a linear or branched alkyl group of C1-C4, for example, methylgroup, ethyl group, isopropyl group, or butyl group,

A is hydrogen or a carbamoyl derivative represented by

B is hydrogen, a carbamoyl derivative represented by

trialkyl silyl groups (e.g., a trimethyl silyl (TMS) group, a triethylsilyl (TES) group, a triisopropyl silyl (TIPS) group, t-butyl dimethylsilyl (TBDMS) group, and the like), trialkylaryl silyl groups (whereinthe total number of alkyl and aryl groups is three; e.g., a t-butyldiphenyl silyl (TBDPS) group and the like), or a trialkyl silyl ethergroup, wherein each alkyl group may be independently selected from thegroup consisting of linear, branched, or cyclic C1-C4 alkyl groups, andeach aryl group may be independently selected from the group consistingof C5-C8 aryl groups, preferably a phenyl group,

A and B are not carbamoyl derivatives at same time, and

R2 and R3 may be the same as or different from each other, andindependently selected from the group consisting of hydrogen, a linearor branched alkyl group of C1-C4, for example C1-C3, a cycloalkyl groupof C3-C8, for example C3-C7, and benzyl group, and more specifically, R2and R3 may be the same as or different from each other, andindependently selected from the group consisting of hydrogen, methylgroup, propyl group, isopropyl group, cyclopropyl group, cyclohexylgroup, bicycloheptane group, and benzyl group.

Another embodiment provides a pharmaceutical composition for ofpreventing and/or treating epilepsy containing a compound of ChemicalFormula 1; a racemate, an enantiomer, a diastereomer, a mixture ofenantiomers, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt thereof, as an active ingredient.

Another embodiment provides a method of preventing and/or treatingepilepsy comprising administering a pharmaceutically effective amount ofa phenyl carbamate compound represented by Chemical Formula 1; aracemate, an enantiomer, a diastereomer, a mixture of enantiomers, or amixture of diastereomers thereof; or a pharmaceutically acceptable saltthereof, to a subject in need of preventing and/or treating epilepsy.

Another embodiment provides a phenyl carbamate compound represented byChemical Formula 1; a racemate, an enantiomer, a diastereomer, a mixtureof enantiomers, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt thereof, for use in the preventionand/or treatment of epilepsy or the manufacture of a pharmaceuticalcomposition for preventing and/or treating epilepsy.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Continuing its research work in the field of epilepsy, the presentinventors, as results of studies on the development of anti-epilepsydrugs, found that a substituted phenyl carbamate compounds of thefollowing Chemical Formula 1 exhibits remarkably excellent anti-epilepsyactivity in various emulation models and simultaneously has very lowtoxicity, and completed the invention.

Therefore, an embodiment provides an organic compound, i.e., phenylcarbamate derivatives, more particularly, a phenyl carbamate compoundrepresented by following Chemical Formula 1; a racemate, an enantiomer,a diastereomer, a mixture of enantiomers, or a mixture of diastereomersthereof; or a pharmaceutically acceptable salt thereof:

wherein,

X is a halogen, for example, chlorine, fluorine, iodine, or bromine,

n, that means the number of substituent X, is an integer from 1 to 5,for example, 1 or 2,

R1 is a linear or branched alkyl group of C1-C4, for example, methylgroup, ethyl group, isopropyl group, or butyl group,

A is hydrogen or a carbamoyl derivative represented by

B is hydrogen, a carbamoyl derivative represented by

trialkyl silyl groups (e.g., a trimethyl silyl (TMS) group, a triethylsilyl (TES) group, a triisopropyl silyl (TIPS) group, t-butyl dimethylsilyl (TBDMS) group, and the like), trialkylaryl silyl groups (whereinthe total number of alkyl and aryl groups is three; e.g., a t-butyldiphenyl silyl (TBDPS) group and the like), or a trialkyl silyl ethergroup, wherein each alkyl group may be independently selected from thegroup consisting of linear, branched, or cyclic C1-C4 alkyl groups, andeach aryl group may be independently selected from the group consistingof C5-C8 aryl groups, preferably a phenyl group,

A and B are not carbamoyl derivatives at same time, and

R2 and R3 may be the same as or different from each other, andindependently selected from the group consisting of hydrogen, a linearor branched alkyl group of C1-C4, for example C1-C3, a cycloalkyl groupof C3-C8, for example C3-C7, and benzyl group, and more specifically, R2and R3 may be the same as or different from each other, andindependently selected from the group consisting of hydrogen, methylgroup, propyl group, isopropyl group, cyclopropyl group, cyclohexylgroup, bicycloheptane group, and benzyl group.

In a concrete embodiment, the phenyl carbamate compound may be selectedfrom the group consisting of:

-   1-(2-chlorophenyl)-1-hydroxypropyl-2-carbamate,-   1-(2-chlorophenyl)-1-hydroxybutyl-2-carbamate,-   1-(2-chlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate,-   1-(2-chlorophenyl)-1-hydroxyhexyl-2-carbamate,-   1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate,-   1-(2-chlorophenyl)-1-hydroxypropyl-2-N-propylcarbamate,-   1-(2-chlorophenyl)-1-hydroxypropyl-2-N-isopropylcarbamate,-   1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclopropylcarbamate,-   1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclohexylcarbamate,-   1-(2-chlorophenyl)-1-hydroxypropyl-2-N-benzylcarbamate,-   1-(2-chlorophenyl)-1-hydroxypropyl-2-N-bicyclo[2,2,1]heptanecarbamate,-   1-(2,4-dichlorophenyl)-1-hydroxypropyl-2-carbamate,-   1-(2,6-dichlorophenyl)-1-hydroxypropyl-2-carbamate,-   1-(2,4-dichlorophenyl)-1-hydroxybutyl-2-carbamate,-   1-(2,6-dichlorophenyl)-1-hydroxybutyl-2-carbamate,-   1-(2,4-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate,-   1-(2,6-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate,-   1-(2,4-dichlorophenyl)-1-hydroxyhexyl-2-carbamate,-   1-(2,6-dichlorophenyl)-1-hydroxyhexyl-2-carbamate,-   1-(2-chlorophenyl)-2-hydroxypropyl-1-carbamate,-   1-(2-chlorophenyl)-2-hydroxypropyl-1-N-methylcarbamate,-   1-(2-chlorophenyl)-2-hydroxypropyl-1-N-propylcarbamate,-   1-(2-chlorophenyl)-2-hydroxypropyl-1-N-isopropylcarbamate,-   1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclopropylcarbamate,-   1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclohexylcarbamate,-   1-(2-chlorophenyl)-2-hydroxypropyl-1-N-benzylcarbamate,-   1-(2,4-dichlorophenyl)-2-hydroxypropyl-1-carbamate,-   1-(2,6-dichlorophenyl)-2-hydroxypropyl-1-carbamate,-   1-(2,4-dichlorophenyl)-2-hydroxybutyl-1-carbamate,-   1-(2,6-dichlorophenyl)-2-hydroxybutyl-1-carbamate,-   1-(2,4-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate,-   1-(2,6-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate,-   1-(2,4-dichlorophenyl)-2-hydroxyhexyl-1-carbamate,-   1-(2,6-dichlorophenyl)-2-hydroxyhexyl-1-carbamate,-   1-(2-fluorophenyl)-1-hydroxypropyl-2-carbamate,-   1-(2-iodophenyl)-1-hydroxypropyl-2-carbamate,-   1-(2-iodophenyl)-1-hydroxybutyl-2-carbamate,-   1-(2,3-dichlorophenyl)-1-hydroxypropyl-2-carbamate, and-   1-(2,3-dichlorophenyl)-2-hydroxypropyl-1-carbamate.

In this compound, 2 chiral carbons exist at positions 1 and 2 fromphenyl group substituted with X; thus, the compound may exist in theform of an enantiomer, a diastereomer, a mixture of enantiomers, or amixture of diastereomers, as well as a racemate.

Alternatively, the compound may be in the form of a pharmaceuticallyacceptable salt. The pharmaceutically acceptable salt may include anadditional salt of acid or base, and its stereochemical isomer. Forexample, the compound may be in the form of an additional salt of anorganic or inorganic acid. The salt may not be specially limited, andinclude any salts that maintain the activities of their parentcompounds, with no undesirable effects, in the subject, when they areadministered to the subject. Such salts may include inorganic andorganic salts, such as salts of acetic acid, nitric acid, aspartic acid,sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid,succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaricacid, hydrobromic acid, propionic acid, benzene sulfonic acid, benzoicacid, stearic acid, lactic acid, bicarbonic acid, bisulfuric acid,bitartaric acid, oxalic acid, butyric acid, calcium edetate, carbonicacid, chlorobezoic acid, citric acid, edetic acid, toluenesulfonic acid,fumaric acid, gluceptic acid, esilic acid, pamoic acid, gluconic acid,methyl nitric acid, malonic acid, hydrochloric acid, hydroiodic,hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelicacid, mucic acid, naphthylic acid, muconic acid, p-nitromethanesulfonicacid, hexamic acid, pantothenic acid, monohydrogen phosphoric acid,dihydrogen phosphoric acid, salicylic acid, sulfamic acid, sulfanilicacid, methane sulfonic acid, and the like. The additional salts of basemay include salts of akali metal or alkaline earth metal, such as saltsof ammonium, lithium, sodium, potassium, magnesium, calcium, and thelike; salts having an organic base, such as benzathine,N-methyl-D-glucamine, hydrabamine, and the like; and salts having anamino acid such as arginine, lysine, and the like. In addition, thesesalts may be converted to a released form by treating with a proper baseor acid.

As demonstrated in the following experimental examples, the compound ofChemical Formula 1; a racemate, an enantiomer, a diastereomer, a mixtureof enantiomers, or a mixture of diastereomers thereof; orpharmaceutically acceptable salt thereof exhibits an excellent effect onpreventing, improving and/or treating epilepsy. Therefore, anotherembodiment provides a pharmaceutical composition for preventing and/ortreating epilepsy containing a phenyl carbamate compound represented byChemical Formula 1; a racemate, an enantiomer, a diastereomer, a mixtureof enantiomers, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt thereof, as an active ingredient.

Another embodiment provides a method of preventing and/or treatingepilepsy comprising administering a pharmaceutically effective amount ofa phenyl carbamate compound represented by Chemical Formula 1; aracemate, an enantiomer, a diastereomer, a mixture of enantiomers, or amixture of diastereomers thereof; or a pharmaceutically acceptable saltthereof, to a subject in need of preventing and/or treating epilepsy.The method may further comprise a step of identifying the subject inneed of preventing and/or treating epilepsy prior to the step ofadministering.

In a concrete embodiment, the epilepsy may include a neurodegeneration(in brain) associated epilepsy. In another concrete embodiment, theepilepsy may not be a muscle spasm associated epilepsy.

The pharmaceutical composition may be formulated in various forms fororal or parenteral administration. For example, the pharmaceuticalcomposition may be formulated in the oral administration form, such as atablet, pill, soft or hard capsule, liquid, suspension, emulsion, syrup,granules, elixirs, and the like. In addition to the active ingredient,the oral administration form may further include pharmaceuticallyacceptable and conventional components, for example, a diluent such aslactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, andthe like; a lubricant such as silica, talc, stearic acid, magnesium orcalcium salt thereof, polyethyleneglycol, and the like.

In the case that the oral administration form is a tablet, it mayfurther include a binder such as magnesium aluminium silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, polyvinylpirrolidine, and the like; andoptionally include one or more additives selected from the groupconsisting of a disintegrant such as starch, agar, arginic acid orsodium salt thereof, an absorbent, a colorant, a flavoring, a sweetener,and the like.

Alternatively, the pharmaceutical composition may also be formulated ina parenteral administration form, which can be administered bysubcutaneous injection, intravenous injection, intramuscular injection,injection into thoracic cavity, and the like. In order to formulate theparenteral administration form, the pharmaceutical composition may beprepared as a solution or suspension wherein the active ingredient isdissolved in water together with a stabilizer and/or a buffering agent,and such solution or suspension formulation may be prepared as a dosageform in ample or vial.

The pharmaceutical composition may be sterilized, and/or include furtheradditives such as a preservative, a stabilizer, a hydrating agent, anemulsification accelerator, a salt and/or buffering agent forosmoregulation, and the like, and/or further therapeutically effectiveingredients. The pharmaceutical composition may be formulated by anyconventional method for mixing, granulating, coating, and the like.

The pharmaceutical composition may be administered to a mammal includinghuman, in the pharmaceutically effective amount of 0.01 to 750 mg/kg(body weight), preferably 0.1 to 500 mg/kg (body weight) per one day,based on the active ingredient. The pharmaceutically effective amountmay refers to an amount capable of exhibiting a desired effect, i.e., aneffect of treating and/or preventing epilepsy. The pharmaceuticallyeffective amount may be administered through oral or parenteral pathway(e.g., an intravenous injection, an intramusclular injection, etc.), oneor two or more times per one day.

The pharmaceutically effective amount and the administration pathway ofthe present pharmaceutical composition may be properly adjusted by aperson skilled in the relevant field considering the conditions of thesubject (patient), desired effects, and the like.

The subject may be a mammal including human or cells and/or tissuesobtained therefrom.

The carbamate compound of the present invention may prepared by thefollowing reaction formula.

A diol compound used in the synthesis of the carbamate compound may besynthesized by dihydroxylation of a trans-olefin compound. A diolcompound having optical activity may be synthesized using a sharplessasymmetric dihydroxylation catalyst.

As indicated in the Reaction Formula II, the optically active substanceof diol may also be synthesized using a reduction reagent aftersynthesizing a hydroxy-ketone compound using Haloro-Mandelic acid. Inthe Reaction Formula II, PG (protecting group) may be selected from thegroup consisting of trialkyl silyl group (e.g., a trimethyl silyl (TMS)group, a triethyl silyl (TES) group, a triisopropyl silyl (TIPS) group,t-butyl dimethyl silyl (TBDMS) group, and the like), trialkylaryl silylgroups (wherein the total number of alkyl and aryl groups is three;e.g., a t-butyl diphenyl silyl (TBDPS) group and the like), estergroup[Ac(acetate), Bz(benzoate), Pv(pivaloate), Cbz(benzyl carbonate),BOC(t-butyl carbonate), Fmoc(9-fluoroenylmethyl)carbaonate, Alloc(allylCarbonate), Troc(trichloroethyl carbonate), p-methoxybenzoate, methylcarbonate, and so on] and the like, wherein each alkyl group may beindependently selected from the group consisting of linear, branched, orcyclic C1-C4 alkyl groups, and each aryl group may be independentlyselected from the group consisting of C5-C8 aryl groups, preferably aphenyl group.

As a highly selectivity form of regioisomer of single carbamate of diolhaving halogen substituent at phenyl ring. (Example 1˜14 and 36˜67 aresynthesized by reaction formula III)

Two substances in the form of regioisomers of a single carbamate of diolhaving halogen substituent at phenyl ring may be separated by flashcolumn chromatography to obtain two kinds of single carbamate compounds.(Example 15˜35 and 68˜115 are synthesized by reaction formula IV)

In the Reaction Formula V, PG(protecting group) may be selected from thegroup consisting of trialkyl silyl group (e.g., a trimethyl silyl (TMS)group, a triethyl silyl (TES) group, a triisopropyl silyl (TIPS) group,t-butyl dimethyl silyl (TBDMS) group, and the like), trialkylaryl silylgroups (wherein the total number of alkyl and aryl groups is three;e.g., a t-butyl diphenyl silyl (TBDPS) group and the like), estergroup[Ac(acetate), Bz(benzoate), Pv(pivaloate), Cbz(benzyl carbonate),BOC(t-butyl carbonate), Fmoc(9-fluoroenylmethyl)carbaonate, Alloc(allylCarbonate), Troc(trichloroethyl carbonate), p-methoxybenzoate, methylcarbonate, and so on] and the like, wherein each alkyl group may beindependently selected from the group consisting of linear, branched, orcyclic C1-C4 alkyl groups, and each aryl group may be independentlyselected from the group consisting of C5-C8 aryl groups, preferably aphenyl group.

In the Reaction Formula IV and V, R4 and R5 may be the same as ordifferent from each other, and independently selected from the groupconsisting of hydrogen, a linear or branched alkyl group of C1-C4, forexample C1-C3, a cycloalkyl group of C3-C8, for example C3-C7, andbenzyl group, and more specifically, R4 and R5 may be the same as ordifferent from each other, and independently selected from the groupconsisting of hydrogen, methyl group, propyl group, isopropyl group,cyclopropyl group, cyclohexyl group, bicycloheptane group, and benzylgroup.

Two substances in the form of regioisomers of a single carbamate of diolhaving halogen substituent at phenyl ring may be separated by flashcolumn chromatography to obtain two kinds of single carbamate compounds.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing ED50 values according to time measured throughMES.

FIG. 2 is a graph showing ED50 values according to time measured throughscPTZ.

EXAMPLE

The present invention is further explained in more detail with referenceto the following examples. These examples, however, should not beinterpreted as limiting the scope of the present invention in anymanner.

Preparation Example 1 Synthesis of 1-(2-chlorophenyl)-trans-1-propene

48 ml of 2-chlorobenzenaldehyde (0.42 mol) and 49.7 ml of 3-pentanone(0.47 mol) were dissolved in 600 mL of hexane in flask, and then stirredwith raising the temperature. 53.6 ml of Boron trifluoride etherate(BF₃OEt₂, 0.42 mol) was added to the resultant under reflux conditions.When the reaction was completed, water was added thereto. After layerseparation, the obtained organic layer was washed twice with 1M sodiumhydroxide solution (1M NaOH), and then the separated organic layer waswashed with water. The separated organic layer was dehydrated withanhydrous magnesium sulfate (MgSO₄) and concentrated. The concentratedresidue was purified by a silica gel column chromatography to producethe title compound (38 g, yield 58%). ¹H NMR (400 MHz, CDCl₃) δ1.94 (d,J=4.8 Hz, 3H), 6.24 (m, 1H), 6.78 (d, J=14 Hz, 1H), 7.11˜7.51 (m, 4H)

Preparation Example 2 Synthesis of 1-(2-chlorophenyl)-trans-1-butene

The substantially same method as described in Preparation Example 1 wasconducted, except that 3-heptanone was used instead of 3-pentanone, toobtain the title compound (2.9 g, yield 83%).

¹H NMR (400 MHz, CDCl₃) δ1.14 (d, J=7.6 Hz, 3H), 2.29˜2.33 (m, 2H), 6.28(dt, J=16 Hz, 6.4 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 7.13˜7.54 (m, 4H)

Preparation Example 3 Synthesis of1-(2-chlorophenyl)-3-methyl-trans-1-butene

The substantially same method as described in Preparation Example 1 wasconducted, except that 2,6-dimethyl-heptan-4-one was used instead of3-pentanone, to obtain the title compound (8.0 g, yield 50˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.14 (d, J=6.8 Hz, 6H), 2.25˜2.57 (m, 1H), 6.20(dd, J=16 Hz, 7.2 Hz, 1H), 7.64 (d, J=16 Hz, 1H), 7.12˜7.54 (m, 4H)

Preparation Example 4 Synthesis of 1-(2-chlorophenyl)-trans-1-hexene

The substantially same method as described in Preparation Example 1 wasconducted, except that 6-undecanone was used instead of 3-pentanone, toobtain the title compound (10 g, yield 85%).

¹H NMR (400 MHz, CDCl₃) δ0.96 (1, J=7.2 Hz, 3H), 1.33˜1.56 (m, 4H),2.26˜2.32 (m, 4H), 6.24 (dt, J=15.6 Hz, 7 Hz, 1H), 6.78 (d, J=16 Hz,1H), 7.13-7.54 (m, 4H)

Preparation Example 5 Synthesis of1-(2,4-dichlorophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 wasconducted, except that 2,4-dichlorobenzenaldehyde was used instead of2-chlorobenzenaldehyde, to obtain the title compound (2.4 g, yield 57%).

¹H NMR (400 MHz, CDCl₃) δ1.95 (dd, J=6.8 Hz, 1.6 Hz, 3H), 6.24 (m, 1H),6.72 (d, J=15.6 Hz, 1H), 7.18˜7.44 (m, 3H)

Preparation Example 6 Synthesis of 1-(2,4-dichlorophenyl)-trans-1-butene

The substantially same method as described in Preparation Example 5 wasconducted, except that 3-heptanone was used instead of 3-pentanone, toobtain the title compound (2.1 g, yield 90%).

¹H NMR (400 MHz, CDCl₃) δ1.14 (d, J=7.6 Hz, 3H), 2.20˜2.33 (m, 2H), 6.26(dt, J=16 Hz, 6.8 Hz, 1H), 6.70 (d, J=15.6 Hz, 1H), 7.18˜7.46 (m, 3H)

Preparation Example 7 Synthesis of1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene

The substantially same method as described in Preparation Example 5 wasconducted, except that 2,6-dimethyl-heptan-4-one was used instead of3-pentanone, to obtain the title compound (0.23 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.8 Hz, 6H), 2.53˜2.58 (m, 1H), 6.19(dd, J=16.4 Hz, 6.8 Hz, 1H), 6.31 (d, J=16.4 Hz, 1H), 7.18˜7.46 (m, 3H)

Preparation Example 8 Synthesis of 1-(2,4-dichlorophenyl)-trans-1-hexene

The substantially same method as described in Preparation Example 5 wasconducted, except that 6-undecanone was used instead of 3-pentanone, toobtain the title compound (3.2 g, yield 40˜80%).

¹H NMR (400 MHz, CDCl₃) δ0.96 (t, J=7.2 Hz, 3H), 1.38˜1.52 (m, 4H),2.25˜2.31 (m, 2H), 6.22 (dt, J=15.6 Hz, 6.8 Hz, 1H), 6.70 (d, J=15.6 Hz,1H), 7.18˜7.46 (m, 3H)

Preparation Example 9 Synthesis of1-(2,6-dichlorophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 wasconducted, except that 2,6-dichlorobenzenaldehyde was used instead of2-chlorobenzenaldehyde, to obtain the title compound (0.4 g, yield10˜40%).

¹H NMR (400 MHz, CDCl₃) δ1.98 (d, J=8 Hz, 3H), 6.23˜6.31 (m, 1H), 6.40(d, J=16 Hz, 1H), 7.05˜7.32 (m, 3H)

Preparation Example 10 Synthesis of1-(2,6-dichlorophenyl)-trans-1-butene

The substantially same method as described in Preparation Example 9 wasconducted, except that 3-heptanone was used instead of 3-pentanone, toobtain the title compound (1.2 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ1.17 (t, J=7.6 Hz, 3H), 2.30˜2.37 (m, 2H), 6.29(dt, J=16.4 Hz, 6 Hz, 1H), 6.37 (d, J=16.4 Hz, 1H), 7.05˜7.32 (m, 3H)

Preparation Example 11 Synthesis of1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene

The substantially same method as described in Preparation Example 9 wasconducted, except that 2,6-dimethyl-heptan-4-one was used instead of3-pentanone, to obtain the title compound (0.23 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.8 Hz, 6H), 2.53˜2.58 (m, 1H), 6.19(dd, J=16.4 Hz, 6.8 Hz, 1H), 6.31 (d, J=16.4 Hz, 1H), 7.05˜7.32 (m, 3H)

Preparation Example 12 Synthesis of1-(2,6-dichlorophenyl)-trans-1-hexene

The substantially same method as described in Preparation Example 9 wasconducted, except that 6-undecanone was used instead of 3-pentanone, toobtain the title compound (0.2 g, yield 10˜40%).

¹H NMR (400 MHz, CDCl₃) δ0.99 (t, J=7.2 Hz, 3H), 1.14˜1.59 (m, 4H),2.30˜2.36 (m, 2H), 6.24 (dt, J=16 Hz, 6.6 Hz, 1H), 6.38 (d, J=16.4 Hz,1H), 7.05˜7.33 (m, 3H)

Preparation Example 13 Synthesis of1-(2,3-dichlorophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 wasconducted, except that 2,3-dichlorobenzenaldehyde was used instead of2-chlorobenzenaldehyde, to obtain the title compound (0.2 g, yield10˜40%).

¹H NMR (400 MHz, CDCl₃) δ1.94 (d, J=4.8 Hz, 3H), 6.24 (m, 1H), 6.78 (d,J=14 Hz, 1H), 7.11˜7.51 (m, 3H)

Preparation Example 14 Synthesis of1-(2-chlorophenyl)-(S,S)-1,2-propanediol

1-(2-chlorophenyl)-trans-1-propene (1.5 g, Preparation Example 1) wasdissolved in 30 mL of the mixture of t-BuOH/H₂O (1:1(V/V)). At 0° C.,AD-mix-α (Aldrich, U.S.A.) (13.7 g) and methane sulfone amide(CH₃SO₂NH₂, 0.76 g, 0.0080 mol) were added thereto and stirred forovernight. When the reaction was completed, the obtained product waswashed with an aqueous solution of sodium sulfite (Na₂SO₃) andethylacetate (EA). Then, the organic layer was dehydrated with anhydrousmagnesium sulfate (MgSO₄), filtrated, and concented under reducedpressure. The concentrated residue was purified by a silica gel columnchromatography to produce the title compound (1.65 g, yield 90%).

¹H NMR (400 MHz, CDCl₃) δ1.20 (d, J=6.4 Hz, 3H), 2.48 (d, J=4.0 Hz 1H),2.92 (d, J=4.4 Hz, 1H), 3.93˜3.97 (m, 1H), 4.97 (t, J=4.8 Hz, 1H),7.22˜7.51 (m, 4H)

¹³CNMR (100 MHz, CDCl₃) δ18.8, 71.5, 74.4, 127.1, 128.1, 128.9, 129.5,132.6, 138.9

Preparation Example 15 Synthesis of1-(2-chlorophenyl)-(R,R)-1,2-propanediol

1-(2-chlorophenyl)-trans-1-propene (2.5 g, Preparation Example 1) wasdissolved in 50 mL of the mixture of t-BuOH/H₂O (1:1(V/V)). At 0° C.,AD-mix-α (Aldrich, U.S.A.) (23.5 g) and methane sulfone amide(CH₃SO₂NH₂, 1.27 g, 0.013 mol) were added thereto and stirred forovernight. When the reaction was completed, the obtained product waswashed with an aqueous solution of sodium sulfite (Na₂SO₃) andethylacetate (EA). Then, the organic layer was dehydrated with anhydrousmagnesium sulfate (MgSO₄), filtrated, and concented under reducedpressure. The concentrated residue was purified by a silica gel columnchromatography to produce the title compound (2.96 g, yield 90%).

¹H NMR (400 MHz, CDCl₃) δ1.20 (d, J=6.4 Hz, 3H), 2.48 (d, J=4.0 Hz, 1H),2.92 (d, J=4.4 Hz, 1H), 3.93˜3.97 (m, 1H), 4.97 (t, J=4.8 Hz, 1H),7.22˜7.51 (m, 4H)

Preparation Example 16 Synthesis of the mixture of1-(2-chlorophenyl)-(S,S)-1,2-propanediol and1-(2-chlorophenyl)-(R,R)-1,2-propanediol

1-(2-chlorophenyl)-trans-1-propene (6.53 g, Preparation Example 1) wasdissolved in 45 mL of the mixture of acetone/t-BuOH/H₂O(5:1:1 V/V). Atthe room temperature, N-methylmorpholine-N-oxide (7.51 g) and OsO₄ (0.54g) were added thereto and stirred for 2-3 hours. When the reaction wascompleted, the obtained product was washed with water andmethylenechloride (MC). Then, the organic layer was dehydrated withanhydrous magnesium sulfate (MgSO₄), filtrated, and concented underreduced pressure. The concentrated residue was purified by a silica gelcolumn chromatography to produce the title compound (6.42 g, yield 80%).

¹H NMR (400 MHz, CDCl₃) δ1.20 (d, J=6.4 Hz, 3H), 2.48 (d, J=4.0 Hz, 1H),2.92 (d, J=4.4 Hz, 1H), 3.93˜3.97 (m, 1H), 4.97 (t, J=4.8 Hz, 1H),7.22˜7.51 (m, 4H)

Preparation Example 17 Synthesis of1-(2-chlorophenyl)-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2-chlorophenyl)-trans-1-butene (PreparationExample 2) was used instead of 1-(2-chlorophenyl)-trans-1-propene(Preparation Example 1), to obtain the title compound (0.36 g, yield95%).

¹H NMR (400 MHz, CDCl₃) δ1.01 (1, J=7.4 Hz, 3H), 1.52˜1.65 (m, 2H), 2.01(d, J=4.4 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H), 3.69˜3.75 (m, 1H), 5.05 (t,J=5.0 Hz, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 18 Synthesis of1-(2-chlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2-chlorophenyl)-trans-1-butene (PreparationExample 2) was used instead of 1-(2-chlorophenyl)-trans-1-propene(Preparation Example 1), to obtain the title compound (0.84 g, yield60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.01 (1, J=7.4 Hz, 3H), 1.52˜1.65 (m, 2H), 2.01(d, J=4.4 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H), 3.69˜3.75 (m, 1H), 5.05 (t,J=5.0 Hz, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 19 Synthesis of the mixture of1-(2-chlorophenyl)-(S,S)-1,2-butanediol and1-(2-chlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2-chlorophenyl)-trans-1-butene (PreparationExample 2) was used instead of 1-(2-chlorophenyl)-trans-1-propene(Preparation Example 1), to obtain the title compound (5.1 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.01 (1, J=7.4 Hz, 3H), 1.52˜1.65 (m, 2H), 2.01(d, J=4.4 Hz, 1H), 2.74 (d, J=5.2 Hz, 1H), 3.69˜3.75 (m, 1H), 5.05 (t,J=5.0 Hz, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 20 Synthesis of1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2-chlorophenyl)-3-methyl-trans-1-butene(Preparation Example 3) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.96 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.07 (1, J=7.2 Hz, 6H), 1.83˜1.89 (m, 1H), 1.92(d, J=5.6 Hz, 1H), 2.69 (d, J=6.4 Hz, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25(m, 1H), 7.23˜7.55 (m, 4H)

Preparation Example 21 Synthesis of1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2-chlorophenyl)-3-methyl-trans-1-butene(Preparation Example 3) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (4.2 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.07 (1, J=7.2 Hz, 6H), 1.82˜1.90 (m, 1H), 1.93(d, J=5.6 Hz, 1H), 2.79 (d, J=6 Hz, 1H), 3.53˜3.57 (m, 1H), 5.23˜5.25(m, 1H), 7.23˜7.54 (m, 4H)

Preparation Example 22 Synthesis of the mixture of1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-butanediol and1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2-chlorophenyl)-3-methyl-trans-1-butene(Preparation Example 3) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.8 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.07 (1, J=7.2 Hz, 6H), 1.83˜1.90 (m, 1H), 1.92(d, J=5.6 Hz, 1H), 2.69 (d, J=6.4 Hz, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25(m, 1H), 7.23˜7.55 (m, 4H)

Preparation Example 23 Synthesis of1-(2-chlorophenyl)-(S,S)-1,2-hexanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2-chlorophenyl)-trans-1-hexene (PreparationExample 4) was used instead of 1-(2-chlorophenyl)-trans-1-propene(Preparation Example 1), to obtain the title compound (0.37 g, yield90%).

¹H NMR (400 MHz, CDCl₃) δ0.90 (t, J=7.2 Hz, 3H), 1.35˜1.65 (m, 6H), 2.08(d, J=4.4 Hz, 1H), 2.71 (d, J=5.2 Hz, 1H), 3.78˜3.83 (m, 1H), 5.04 (t,J=5.0 Hz, 1H), 7.23˜7.53 (m, 4H)

Preparation Example 24 Synthesis of1-(2-chlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2-chlorophenyl)-trans-1-hexene (PreparationExample 4) was used instead of 1-(2-chlorophenyl)-trans-1-propene(Preparation Example 1), to obtain the title compound (4.2 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.91 (1, J=6.6 Hz, 3H), 1.35˜1.65 (m, 6H), 2.08(d, J=4.8 Hz, 1H), 2.70 (d, J=5.2 Hz, 1H), 3.80˜3.83 (m, 1H), 5.05 (t,J=5.0 Hz, 1H), 7.24˜7.56 (m, 4H)

Preparation Example 25 Synthesis of the mixture of1-(2-chlorophenyl)-(S,S)-1,2-hexanediol and1-(2-chlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2-chlorophenyl)-trans-1-hexene (PreparationExample 4) was used instead of 1-(2-chlorophenyl)-trans-1-propene(Preparation Example 1), to obtain the title compound (7.9 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.90 (t, J=7.2 Hz, 3H), 1.26˜1.55 (m, 6H), 2.08(d, J=4.4 Hz, 1H), 2.71 (d, J=5.6 Hz, 1H), 3.78˜3.84 (m, 1H), 5.04 (t,J=3.2 Hz, 1H), 7.24˜7.55 (m, 4H)

Preparation Example 26 Synthesis of1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2,4-dichlorophenyl)-trans-1-propene(Preparation Example 5) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.33 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.22 (d, J=6.4 Hz, 3H), 2.10 (d, J=4.4 Hz, 1H),2.71 (d, J=4.8 Hz, 1H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H), 7.31(dd, J=2.0 Hz, J=8.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.4 Hz,1H)

Preparation Example 27 Synthesis of1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2,4-dichlorophenyl)-trans-1-propene(Preparation Example 5) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.45 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.22 (d, J=6.4 Hz, 3H), 2.10 (d, J=4.4 Hz, 1H),2.71 (d, J=4.8 Hz, 1H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H),7.31˜7.49 (m, 3H)

Preparation Example 28 Synthesis of the mixture of1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol and1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2,4-dichlorophenyl)-trans-1-propene(Preparation Example 5) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.45 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.22 (d, J=6.4 Hz, 3H), 2.10 (d, J=4.4 Hz, 1H),2.71 (d, J=4.8 Hz, 1H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H),7.31˜7.49 (m, 3H)

Preparation Example 29 Synthesis of1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2,4-dichlorophenyl)-trans-1-butene(Preparation Example 6) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.32 g, yield 90%).

¹H NMR (400 MHz, CDCl₃) δ1.02 (1, J=7.4 Hz, 3H), 1.54˜1.61 (m, 2H), 2.07(d, J=4.8 Hz, 1H), 2.74 (d, J=4.8 Hz, 1H), 3.65˜3.68 (m, 1H), 5.01 (t,J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 30 Synthesis of1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2,4-dichlorophenyl)-trans-1-butene(Preparation Example 6) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.43 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.02 (1, J=7.4 Hz, 3H), 1.54˜1.61 (m, 2H), 2.07(d, J=4.8 Hz, 1H), 2.74 (d, J=4.8 Hz, 1H), 3.65˜3.68 (m, 1H), 5.01 (t,J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 31 Synthesis of the mixture of1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol and1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2,4-dichlorophenyl)-trans-1-butene(Preparation Example 6) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.33 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.02 (1, J=7.4 Hz, 3H), 1.54˜1.61 (m, 2H), 2.07(d, J=4.8 Hz, 1H), 2.74 (d, J=4.8 Hz, 1H), 3.65˜3.68 (m, 1H), 5.01 (t,J=5.0 Hz, 1H), 77.31˜7.49 (m, 3H)

Preparation Example 32 Synthesis of1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2,4-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 7) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.25 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t,J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 33 Synthesis of1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2,4-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 7) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.36 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t,J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 34 Synthesis of the mixture of1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol and1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2,4-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 7) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.26 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t,J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 35 Synthesis of1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2,4-dichlorophenyl)-trans-1-hexene(Preparation Example 8) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (1.1 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.89˜0.93 (m, 3H), 1.30˜1.39 (m, 2H), 1.49˜1.52(m, 2H), 1.56˜1.62 (m, 2H), 2.05 (d, J=5.2 Hz, 1H), 2.74 (d, J=5.2 Hz,1H), 3.72˜3.77 (m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 36 Synthesis of1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2,4-dichlorophenyl)-trans-1-hexene(Preparation Example 8) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (1.2 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ0.89˜0.93 (m, 3H), 1.30˜1.39 (m, 2H), 1.49˜1.52(m, 2H), 1.56˜1.62 (m, 2H), 2.05 (d, J=5.2 Hz, 1H), 2.74 (d, J=5.2 Hz,1H), 3.72˜3.77 (m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 37 Synthesis of the mixture of1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol and1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2,4-dichlorophenyl)-trans-1-hexene(Preparation Example 8) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.67 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ0.89˜0.93 (m, 3H), 1.30˜1.39 (m, 2H), 1.49˜1.52(m, 2H), 1.56˜1.62 (m, 2H), 2.05 (d, J=5.2 Hz, 1H), 2.74 (d, J=5.2 Hz,1H), 3.72˜3.77 (m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 38 Synthesis of1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2,6-dichlorophenyl)-trans-1-propene(Preparation Example 9) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.9 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H),3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H),7.18˜7.36 (m, 3H)

Preparation Example 39 Synthesis of1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2,6-dichlorophenyl)-trans-1-propene(Preparation Example 9) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.84 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H),3.10 (d, J=8.4 Hz, 1H), 4.47-4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H),7.18˜7.36 (m, 3H)

Preparation Example 40 Synthesis of the mixture of1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol and1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2,6-dichlorophenyl)-trans-1-propene(Preparation Example 9) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.91 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H),3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H),7.18˜7.36 (m, 3H)

Preparation Example 41 Synthesis of1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2,6-dichlorophenyl)-trans-1-butene(Preparation Example 10) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (1.23 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ0.97 (t, J=7.6 Hz, 3H), 1.26˜1.53 (m, 2H), 2.64(dd, J=0.8 Hz, J=4.0 Hz, 1H), 3.14 (d, J=8.4 Hz, 1H), 4.22˜4.26 (m, 1H),5.26 (t, J=8.4 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 42 Synthesis of1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2,6-dichlorophenyl)-trans-1-butene(Preparation Example 10) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.96 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ0.97 (t, J=7.6 Hz, 3H), 1.26˜1.53 (m, 2H), 2.64(dd, J=0.8 Hz, J=4.0 Hz, 1H), 3.14 (d, J=8.4 Hz, 1H), 4.22˜4.26 (m, 1H),5.26 (t, J=8.4 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 43 Synthesis of the mixture of1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol and1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2,6-dichlorophenyl)-trans-1-butene(Preparation Example 10) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.86 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ0.97 (t, J=7.6 Hz, 3H), 1.26˜1.53 (m, 2H), 2.64(dd, J=0.8 Hz, J=4.0 Hz, 1H), 3.14 (d, J=8.4 Hz, 1H), 4.22˜4.26 (m, 1H),5.26 (t, J=8.4 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 44 Synthesis of1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 11) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.25 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t,J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 45 Synthesis of1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 11) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.37 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t,J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 46 Synthesis of the mixture of1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol and1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2,6-dichlorophenyl)-3-methyl-trans-1-butene(Preparation Example 11) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.47 g, yield 60˜95%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (d, J=6.8 Hz, 6H), 1.60˜1.65 (m, 1H), 2.35(d, J=4.0 Hz, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.13˜4.18 (m, 1H), 5.36 (t,J=7.6 Hz, 1H), 7.17˜7.35 (m, 3H)

Preparation Example 47 Synthesis of1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2,6-dichlorophenyl)-trans-1-hexene(Preparation Example 12) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.36 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.85 (t, J=6.8 Hz, 3H), 1.20˜1.31 (m, 4H),1.45˜1.53 (m, 2H), 2.61˜2.62 (m, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.28˜4.33(m, 1H), 5.25 (t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 48 Synthesis of1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2,6-dichlorophenyl)-trans-1-hexene(Preparation Example 12) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.58 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.85 (t, J=6.8 Hz, 3H), 1.20˜1.31 (m, 4H),1.45˜1.53 (m, 2H), 2.61˜2.62 (m, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.28˜4.33(m, 1H), 5.25 (t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 49 Synthesis of the mixture of1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol and1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2,6-dichlorophenyl)-trans-1-hexene(Preparation Example 12) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.62 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.85 (t, J=6.8 Hz, 3H), 1.20˜1.31 (m, 4H),1.45˜1.53 (m, 2H), 2.61˜2.62 (m, 1H), 3.12 (d, J=8.4 Hz, 1H), 4.28˜4.33(m, 1H), 5.25 (t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 50 Synthesis of methyl2-(2-chlorophenyl)-(R)-2-hydroxyacetate

15 g of (R)-2-chloromandelic acid was mixed with methanol (CH₃OH, 150ml) and phosphorus chloride oxide (POCl₃, 0.76 ml) in a flask bystiffing using a magnetic stirrer at the room temperature for 6 hours.When the reaction was completed, the obtained product was washed with anaqueous solution of sodium sulfite (Na₂SO₃) and ethylacetate (EA). Then,the organic layer was dehydrated with anhydrous magnesium sulfate(MgSO₄), filtrated, and concented under reduced pressure. Theconcentrated residue was purified by a silica gel column chromatographyto produce the title compound (15.64 g, yield 95%).

¹H NMR (400 MHz, CDCl₃) δ 3.59 (d, J=5.2, 1H), 3.79 (t, J=6.0, 3H), 5.59(d, J=5.2, 1H), 7.28˜7.43 (m, 4H)

Preparation Example 51 Synthesis of2-(2-chlorophenyl)-(R)-2-hydroxy-N-methoxy-N-methylacetamide

N,O-dimethylhydroxylamine hydrochloride (N,O-dimethylhydroxylamine.HCl,15.2 g) was dissolved in dichloromethane (DCM, 150 ml), and cooled to 0°C. using an ice-bath. Then, 77.7 ml of 2.0M trimethylaluminium in hexanewas slowly added thereto in drop-wise manner for 30 minutes. Thereafter,the ice-bath was removed, and the obtained product was stirred at theroom temperature for 2 hours.Methyl-2-(2-chlorophenyl)-(R)-2-hydroxyacetate (15.64 g) dissolved indichloromethane (DCM, 150 ml) was added in drop-wise manner thereto atthe room temperature for 30 minutes, and subjected to reflux for 12hours. When the reaction was completed, the obtained product was cooledto 0° C., and washed by a slow drop-wise addition of hydrochloric acid(HCl, 200 ml). The obtained organic layer was washed with distilledwater and brine, dehydrated with anhydrous magnesium sulfate (MgSO₄),filtrated, and concented under reduced pressure. The concentratedresidue was purified by a silica gel column chromatography to producethe title compound (14.68 g, yield 82%).

¹H NMR (400 MHz, CDCl₃) δ3.23 (s, 3H), 3.28 (s, 3H), 4.33 (d, J=6.0 Hz,1H), 5.81 (d, J=5.6 Hz, 1H), 7.23˜7.42 (m, 4H)

Preparation Example 52 Synthesis of2-(2-chlorophenyl)-N-methoxy-(R)-2-(t-butyldimethlysiloxy)-N-methylacetamide

2-(2-chlorophenyl)-(R)-2-hydroxy-N-methoxy-N-methylacetamide (0.81 g,3.52 mmol) obtained in Preparation Example 51 was dissolved indichloromethane (DCM), and cooled to 0° C. Imedazole (0.36 g, 5.28 mmol)was slowly added, and stirred. TBDMS-Cl (t-butyldimethylsily chloride,0.79 g, 5.28 mmol) was slowly added. When the reaction was completed,the reaction mixture was quenched with H₂O. The organic layer wasseparated and collected. The aqueous layer was extracted with CH₂Cl₂(300 mL), dried over MgSO₄. Concentration under vacuum provided a titlecompound. (0.97 g, 80˜95%).

¹H NMR (400 MHz, CDCl₃) δ−0.03 (s, 3H), 0.14 (s, 3H), 0.94 (s, 9H), 2.97(s, 3H), 3.02 (s, 3H), 5.83 (s, 1H), 7.25˜7.60 (m, 4H)

Preparation Example 53 Synthesis of1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)propane-2-on

2-(2-chlorophenyl)-N-methoxy-(R)-2-(t-butyldimethylsiloxy)-N-methylacetamide(0.9 g) obtained in Preparation Example 52 was dissolved intetrahydrofuran (THF), and cooled to 0° C. 3.0M methyl magnesium bromide(MeMgBr, 2.18 ml) solution in ether was added thereto in drop-wisemanner for 30 minutes, and the obtained product was stirred at 0° C.When the reaction was completed, diethylether was added thereto. Theobtained product was washed with 10% (w/v) potassium hydrogen sulfate(KHSO₄, 100 ml) and then, washed again with brine. The obtained organiclayer was dehydrated with anhydrous magnesium sulfate (MgSO₄),filtrated, and concentrated under reduced pressure. The concentratedresidue was purified by a silica gel column chromatography to producethe title compound (0.69 g, yield 85˜95%).

¹H NMR (400 MHz, CDCl₃) δ−0.3 (s, 3H), 0.14 (s, 3H), 0.94 (s, 9H), 2.18(s, 3H), 5.50 (s, 1H), 7.27˜7.56 (m, 4H)

Preparation Example 54 Synthesis of1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)-(S)-2-propanol

1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)propane-2-on (0.14 g)obtained in Preparation Example 53 was dissolved in ether, and cooled to−78° C. Zinc borohydride(Zn(BH₄)₂) was slowly added thereto and theobtained product was stirred. When the reaction was completed, theobtained product was washed by H₂O. The obtained organic layer waswashed with H₂O, dehydrated with anhydrous magnesium sulfate (MgSO₄),filtrated, and concentrated under reduced pressure. The concentratedresidue was purified by a silica gel column chromatography to producethe title compound (0.04 g, yield 25˜33%, cis:trans=2:1).

¹H NMR (400 MHz, CDCl₃) δ−0.11 (s, 3H), 0.11 (s, 3H), 0.93 (S, 9H), 1.07(d, J=6.4 3H), 2.05 (d, J=6.4 1H), 4.01˜4.05 (m, 1H), 5.18 (d, J=4.0,1H), 7.20˜7.56 (m, 4H))

Preparation Example 55 Synthesis of1-(2-chlorophenyl)-(R,S)-1,2-propanediol

1-(2-chlorophenyl)-(R)-1-(t-butyldimethyl-siloxy)-(S)-2-propanol (10.38g) obtained in Preparation Example 54 was dissolved in methanol (CH₃OH,100 ml), and then, cooled to 0° C. 8M hydrochloric acid (HCl, 56.2 ml)was slowly added in drop-wise manner to the obtained product, and then,the obtained product was warmed to the room temperature, and stirred for15 hours. When the reaction was completed, the obtained product wascooled to 0° C. 5N sodium hydroxide (NaOH, 30 ml) was slowly addedthereto, and the obtained product was subjected to vacuum concentration.The obtained product was diluted with ethylacetate. The obtained organiclayer was washed with distilled water, dehydrated with anhydrousmagnesium sulfate (MgSO₄), filtrated, and concented under reducedpressure. The concentrated residue was purified by a silica gel columnchromatography to produce the title compound (7.05 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.07 (d, J=6.8, 3H), 2.01 (d, J=5.6, 1H), 2.61(s, 1H), 4.21˜4.27 (m, 1H), 5.24 (d, J=3.6, 1H), 7.22˜7.64 (m, 4H)

Preparation Example 56 Synthesis of1-(2-chlorophenyl)-(S,R)-1,2-propanediol

The substantially same method as described in Preparation Example 50˜55was conducted, except that (S)-2-chloromandelic acid was used instead of(R)-2-chloromandelic acid, to obtain the title compound (5.04 g, yield84%).

¹H NMR (400 MHz, CDCl₃) δ1.07 (d, J=6.8, 3H), 2.00 (d, J=5.6, 1H), 2.54(d, J=3.6, 1H), 4.22˜4.26 (m, 1H), 5.25 (t, J=3.2, 1H), 7.22˜7.65 (m,4H)

Preparation Example 57 Synthesis of1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2,3-dichlorophenyl)-trans-1-propene(Preparation Example 13) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.9 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H),3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜(m, 3H)

Preparation Example 58 Synthesis of1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2,3-dichlorophenyl)-trans-1-propene(Preparation Example 13) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.84 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H),3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜(m, 3H)

Preparation Example 59 Synthesis of the mixture of1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol and1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 16 wasconducted, except that 1-(2,3-dichlorophenyl)-trans-1-propene(Preparation Example 13) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (0.91 g, yield 60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.10 (d, J=6.4 Hz, 3H), 2.72 (d, J=2.4 Hz, 1H),3.10 (d, J=8.4 Hz, 1H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H),7.18˜(m, 3H)

Preparation Example 60 Synthesis of 1-(2-fluorophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 wasconducted, except that 2-fluorobenzenaldehyde was used instead of2-chlorobenzenealdehyde, to obtain the title compound (6.67 g, yield61%).

¹H NMR (400 MHz, CDCl₃) δ1.94 (d, J=6.8 Hz, 3H), 6.30˜6.38 (m, 1H), 6.57(d, J=16 Hz, 1H), 7.00˜7.41 (m, 4H)

Preparation Example 61 Synthesis of1-(2-fluorophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2-fluorophenyl)-trans-1-propene (PreparationExample 60) was used instead of 1-(2-chlorophenyl)-trans-1-propene(Preparation Example 1), to obtain the title compound (6.46 g, yield78%).

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 2.43 (d, J=3.6 Hz, 1H),2.69 (d, J=4.8 Hz, 1H), 3.90˜3.98 (m, 1H), 4.78 (dd, J=4.4, 7.2 Hz, 1H),7.04˜7.50 (m, 4H)

Preparation Example 62 Synthesis of1-(2-fluorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 wasconducted, except that 1-(2-fluorophenyl)-trans-1-propene (PreparationExample 60) was used instead of 1-(2-chlorophenyl)-trans-1-propene(Preparation Example 1), to obtain the title compound (3.29 g, yield79%).

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 2.43 (d, J=3.6 Hz, 1H),2.69 (d, J=4.8 Hz, 1H), 3.90˜3.98 (m, 1H), 4.78 (dd, J=4.4, 7.2 Hz, 1H),7.04˜7.50 (m, 4H)

Preparation Example 63 Synthesis of 2-iodobenzenealdehyde

In a flask, 2-iodobenzyl alcohol (4 g, 17.09 mmol) was dissolved indichloromethane (MC, 85 ml), and then, manganese oxide (MnO₂, 14.86 g,170.92 mmol) was added thereto. The obtained reaction product wasstirred under the reflux condition. When the reaction was completed, theobtained reaction product was cooled to the room temperature, and then,fiteated and concentrated using celite, to obtain the title compound(3.6 g, yield 91%).

¹H NMR (400 MHz, CDCl₃) δ7.30˜7.99 (m, 4H), 10.10 (s, 1H)

Preparation Example 64 Synthesis of 1-(2-iodophenyl)-trans-1-propene

The substantially same method as described in Preparation Example 1 wasconducted, except that 2-iodobenzenealdehyde (Preparation Example 63)was used instead of 2-chlorobenzenealdehyde, to obtain the titlecompound (3.4 g, yield 65%).

¹H NMR (400 MHz, CDCl₃) δ1.95 (dd, J=6.8 Hz, 1.6 Hz, 3H), 6.09˜6.18 (m,1H), 6.60 (dd, J=15.66 Hz, 1.8 Hz, 1H), 6.89˜7.84 (m, 4H)

Preparation Example 65 Synthesis of 1-(2-iodophenyl)-trans-1-butene

The substantially same method as described in Preparation Example 64 wasconducted, except that 3-heptanone was used instead of 3-pentanone, toobtain the title compound (8.5 g, yield 75%).

¹H NMR (400 MHz, CDCl₃) δ1.46 (t, J=7.6 Hz, 3H), 2.26˜2.34 (m, 2H), 6.17(dt, J=15.6 Hz, 6.6 Hz 1H), 6.57 (d, J=15.6 Hz, 1H), 6.89˜7.85 (m, 4H)

Preparation Example 66 Synthesis of1-(2-iodophenyl)-(S,S)-1,2-propanediol

The substantially same method as described in Preparation Example 14 wasconducted, except that 1-(2-iodophenyl)-trans-1-propene (PreparationExample 64) was used instead of 1-(2-chlorophenyl)-trans-1-propene(Preparation Example 1), to obtain the title compound (3.4 g, yield88%).

¹H NMR (400 MHz, CDCl₃) δ1.27 (d, J=6.4 Hz, 3H), 2.26 (br s, 1H), 2.74(br s, 1H), 3.99 (t, J=6.0 Hz, 1H), 4.81 (d, J=4.0 Hz, 1H), 7.01˜7.87(m, 4H)

Preparation Example 67 Synthesis of1-(2-iodorophenyl)-(R,R)-1,2-propanediol

The substantially same method as described in Preparation Example 15 wasconducted was conducted, except that 1-(2-iodophenyl)-trans-1-propene(Preparation Example 64) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (7.4 g, yield 84%).

¹H NMR (400 MHz, CDCl₃) δ1.26 (d, J=6.4 Hz, 3H), 2.35 (br s, 1H), 2.85(br d, J=4.0 Hz, 1H), 3.98 (t, J=6.2 Hz, 1H), 4.80 (dd, J=5.0, 4.4 Hz,1H), 7.00˜7.87 (m, 4H)

Preparation Example 68 Synthesis of1-(2-iodophenyl)-(S,S)-1,2-butanediol

The substantially same method as described in Preparation Example 14 wasconducted was conducted, except that 1-(2-iodophenyl)-trans-1-butene(Preparation Example 65) was used instead of1-(2-chlorophenyl)-trans-1-propene (Preparation Example 1), to obtainthe title compound (9.5 g, yield 84%).

¹H NMR (400 MHz, CDCl₃) δ1.04 (t, J=7.6 Hz, 3H), 1.60˜1.71 (m, 2H), 2.07(br s, 1H), 2.74 (br s, 1H), 3.71˜3.76 (m, 1H), 4.87 (d, J=4.8 Hz, 1H),7.01˜7.87 (m, 4H)

Preparation Example 69 Preparation of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane

To a stirred solution of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14, 67 g, 0.35 mol) in CH₂Cl₂ (670 ml) was addedEt₃N (200 mL, 1.43 mol) and TMSCl (113.9 mL, 0.89 mol) at 0° C. underN₂. The reaction mixture was allowed to stir at 0° C. for 3 hr. Thereaction mixture was quenched with H₂O (650 mL) at 0° C. The organiclayer was separated and collected. The aqueous layer was extracted withCH₂Cl₂ (300 mL), dried over MgSO₄. Concentration under vacuum provided acrude product. 104.18 g (117.44%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, J=6.4 Hz, 1H), 7.207˜7.165 (m,1H), 7.321˜7.245 (m, 2H), 7.566˜7.543 (m, 1H)

Preparation Example 70 Preparation of1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-propanediol(Preparation example 15) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (8.5 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, J=6.4 Hz, 1H), 7.21˜7.54 (m, 4H)

Preparation Example 71 Preparation of1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)propane-1,2-diol (Preparationexample 16) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14) to obtain the title compound (5.2 g, yield90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, J=6.4 Hz, 1H), 7.21˜7.54 (m, 4H)

Preparation Example 72 Preparation of1-(2-chlorophenyl)-(S,R)-1,2-(Bis-trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-(S,R)-1,2-propanediol(Preparation example 56) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.4 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, J=6.4 Hz, 1H), 7.21-7.54 (m, 4H)

Preparation Example 73 Preparation of1-(2-chlorophenyl)-(R,S)-1,2-(Bis-trimethylsilanyloxy) propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-(R,S)-1,2-propanediol(Preparation example 55) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.2 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=5.6Hz, 3H), 3.977˜3.918 (m, 1H), 4.973 (d, J=6.4 Hz, 1H), 7.21˜7.54 (m, 4H)

Preparation Example 74 Preparation of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-(S,S)-1,2-butanediol(Preparation example 17) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.01 (t, J=7.4Hz, 3H), 1.52˜1.65 (m, 2H), 3.69˜3.75 (m, 1H), 5.05 (t, J=5.0 Hz, 1H),7.23˜7.54 (m, 4H)

Preparation Example 75 Preparation of1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy) butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-butanediol(Preparation example 18) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.5 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.01 (t, J=7.4Hz, 3H), 1.52˜1.65 (m, 2H), 3.69˜3.75 (m, 1H), 5.05 (t, J=5.0 Hz, 1H),7.23˜7.54 (m, 4H)

Preparation Example 76 Preparation of1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy) butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-1,2-butanediol (Preparationexample 19) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14) to obtain the title compound (3.0 g, yield90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.01 (t, J=7.4Hz, 3H), 1.52˜1.65 (m, 2H), 3.69˜3.75 (m, 1H), 5.05 (t, J=5.0 Hz, 1H),7.23˜7.54 (m, 4H)

Preparation Example 77 Preparation of1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-butanediol(Preparation example 20) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title (2.7 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.07 (t, J=7.2Hz, 6H), 1.83˜1.89 (m, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25 (m, 1H),7.23˜7.55 (m, 4H)

Preparation Example 78 Preparation of1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-butanediol(Preparation example 21) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.4 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.07 (t, J=7.2Hz, 6H), 1.83˜1.89 (m, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25 (m, 1H),7.23˜7.55 (m, 4H)

Preparation Example 79 Preparation of1-(2-chlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-3-methyl-1,2-butanediol(Preparation example 22) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.07 (t, J=7.2Hz, 6H), 1.83˜1.89 (m, 1H), 3.53˜3.56 (m, 1H), 5.22˜5.25 (m, 1H),7.23˜7.55 (m, 4H)

Preparation Example 80 Preparation of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-(S,S)-1,2-hexanediol(Preparation example 23) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.90 (t, J=7.2Hz, 3H), 1.35˜1.65 (m, 6H), 3.78˜3.83 (m, 1H), 5.04 (t, J=5.0 Hz, 1H),7.23˜7.53 (m, 4H)

Preparation Example 81 Preparation of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-(R,R)-1,2-hexanediol(Preparation example 24) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.3 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.90 (t, J=7.2Hz, 3H), 1.35˜1.65 (m, 6H), 3.78˜3.83 (m, 1H), 5.04 (t, J=5.0 Hz, 1H),7.23˜7.53 (m, 4H)

Preparation Example 82 Preparation of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-chlorophenyl)-1,2-hexanediol (Preparationexample 25) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14) to obtain the title compound (3.2 g, yield90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.90 (t, J=7.2Hz, 3H), 1.35˜1.65 (m, 6H), 3.78˜3.83 (m, 1H), 5.04 (t, J=5.0 Hz, 1H),7.23˜7.53 (m, 4H)

Preparation Example 83 Preparation of1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol(Preparation example 26) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.4 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.22 (d, J=6.4Hz, 3H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H), 7.31 (dd, J=2.0 Hz,J=8.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H)

Preparation Example 84 Preparation of1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol(Preparation example 38) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.4 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.13˜7.36 (m, 3H)

Preparation Example 85 Preparation of1-(2,3-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol(Preparation example 57) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.2 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4Hz, 3H,), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.22 (m, 3H)

Preparation Example 86 Preparation of1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol(Preparation example 29) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.02 (t, J=7.4Hz, 3H), 1.54˜1.61 (m, 2H), 3.65˜3.68 (m, 1H), 5.01 (t, J=5.0 Hz, 1H),7.31˜7.49 (m, 3H)

Preparation Example 87 Preparation of1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol(Preparation example 41) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.97 (t, J=7.6Hz, 3H), 1.26˜1.53 (m, 2H), 4.22˜4.26 (m, 1H), 5.26 (t, J=8.4 Hz, 1H),7.17˜7.35 (m, 3H)

Preparation Example 88 Preparation of1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparationexample 32) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14) to obtain the title compound (2.7 g, yield90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H),7.30˜7.53 (m, 3H)

Preparation Example 89 Preparation of1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol (Preparationexample 44) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14) to obtain the title compound (3.3 g, yield90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H),7.17˜7.35 (m, 3H)

Preparation Example 90 Preparation of1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol(Preparation example 90) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.89˜0.93 (m,3H), 1.30˜1.39 (m, 2H), 1.49˜1.52 (m, 2H), 1.56˜1.6 (m, 2H), 3.72˜3.77(m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 91 Preparation of1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol(Preparation example 47) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.85 (t, J=6.7Hz, 3H), 1.20˜1.31 (m, 4H), 1.45˜1.53 (m, 2H), 4.28˜4.33 (m, 1H), 5.25(t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 92 Preparation of1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol(Preparation example 27) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.2 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.22 (d, J=6.4Hz, 3H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 93 Preparation of1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol(Preparation example 39) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.36 (m, 3H)

Preparation Example 94 Preparation of1-(2,3-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol(Preparation example 58) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.9 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.22 (m, 3H)

Preparation Example 95 Preparation of1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol(Preparation example 30) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.02 (t, J=7.4Hz, 3H), 1.54˜1.61 (m, 2H), 3.65˜3.68 (m, 1H), 5.01 (t, J=5.0 Hz, 1H),7.31˜7.49 (m, 3H)

Preparation Example 96 Preparation of1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol(Preparation example 42) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.3 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.97 (t, J=7.6Hz, 3H), 1.26˜1.53 (m, 2H), 4.22˜4.26 (m, 1H), 5.26 (t, J=8.4 Hz, 1H),7.17˜7.35 (m, 3H)

Preparation Example 97 Preparation of1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol (Preparationexample 33) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14) to obtain the title compound (3.5 g, yield90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H),7.30˜7.53 (m, 3H)

Preparation Example 98 Preparation of1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-butanediol (Preparationexample 45) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14) to obtain the title compound (3.4 g, yield90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H),7.17˜7.35 (m, 3H)

Preparation Example 99 Preparation of1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol(Preparation example 36) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.89˜0.93 (m,3H), 1.30˜1.39 (m, 2H), 1.49˜1.52 (m, 2H), 1.56˜1.62 (m, 2H), 3.72˜3.77(m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 100 Preparation of1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol(Preparation example 48) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.3 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.85 (t, J=6.7Hz, 3H), 1.20˜1.31 (m, 4H), 1.45˜1.53 (m, 2H), 4.28˜4.33 (m, 1H), 5.25(t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 101 Preparation of1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-1,2-propanediol(Preparation example 28) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.22 (d, J=6.4Hz, 3H), 3.90˜3.95 (m, 1H), 4.94 (t, J=5.0 Hz, 1H), 7.31˜7.49 (m, 3H)

Preparation Example 102 Preparation of1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-1,2-propanediol(Preparation example 40) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.36 (m, 3H)

Preparation Example 103 Preparation of1-(2,3-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,3-dichlorophenyl)-1,2-propanediol(Preparation example 59) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.7 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.10 (d, J=6.4Hz, 3H), 4.47˜4.54 (m, 1H), 5.24 (t, J=8.8 Hz, 1H), 7.18˜7.22 (m, 3H)

Preparation Example 104 Preparation of1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-1,2-butanediol(Preparation example 31) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.9 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.02 (t, J=7.4Hz, 3H), 1.54˜1.61 (m, 2H), 3.65˜3.68 (m, 1H), 5.01 (t, J=5.0 Hz, 1H),7.31˜7.49 (m, 3H)

Preparation Example 105 Preparation of1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-1,2-butanediol(Preparation example 43) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.97 (t, J=7.6Hz, 3H), 1.26˜1.53 (m, 2H), 4.22˜4.26 (m, 1H), 5.26 (t, J=8.4 Hz, 1H),7.17˜7.35 (m, 3H)

Preparation Example 106 Preparation of1-(2,4-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-3-methyl-1,2-butanediol(Preparation example 34) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.7 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H),7.30˜7.53 (m, 3H)

Preparation Example 107 Preparation of1-(2,6-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-3-methyl-1,2-butanediol(Preparation example 46) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.6 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.00 (d, J=6.8Hz, 6H), 1.60˜1.65 (m, 1H), 4.13˜4.18 (m, 1H), 5.36 (t, J=7.6 Hz, 1H),7.17˜7.35 (m, 3H)

Preparation Example 108 Preparation of1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,4-dichlorophenyl)-1,2-hexanediol(Preparation example 37) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.7 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.89˜0.93 (m,3H), 1.30˜1.39 (m, 2H), 1.49˜1.52 (m, 2H), 1.56˜1.62 (m, 2H), 3.72˜3.77(m, 1H), 4.98 (t, J=4.8 Hz, 1H), 7.28˜7.50 (m, 3H)

Preparation Example 109 Preparation of1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)-hexane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2,6-dichlorophenyl)-1,2-hexanediol(Preparation example 49) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.2 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 0.85 (t, J=6.7Hz, 3H), 1.20˜1.31 (m, 4H), 1.45˜1.53 (m, 2H), 4.28˜4.33 (m, 1H), 5.25(t, J=8.4 Hz, 1H), 7.18˜7.35 (m, 3H)

Preparation Example 110 Preparation of1-(2-fluoroophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-fluoroophenyl)-(S,S)-1,2-propanediol(Preparation example 61) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=6.4Hz, 3H), 3.90˜3.98 (m, 1H), 4.78 (dd, J=4.4, 7.2 Hz, 1H), 7.04˜7.50 (m,4H)

Preparation Example 111 Preparation of1-(2-fluorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-fluoroophenyl)-(R,R)-1,2-propanediol(Preparation example 62) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.5 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.15 (d, J=6.4Hz, 3H), 3.90˜3.98 (m, 1H), 4.78 (dd, J=4.4, 7.2 Hz, 1H), 7.04˜7.50 (m,4H)

Preparation Example 112 Preparation of1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-iodophenyl)-(S,S)-1,2-propanediol(Preparation example 66) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.1 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.27 (d, J=6.4Hz, 3H), 3.99 (t, J=6.0 Hz, 1H), 4.81 (d, J=4.0 Hz, 1H), 7.01˜7.87 (m,4H)

Preparation Example 113 Preparation of1-(2-iodophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)-propane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-iodophenyl)-(R,R)-1,2-propanediol(Preparation example 67) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (2.8 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.26 (d, J=6.4Hz, 3H), 3.98 (t, J=6.2 Hz, 1H), 4.88 (d, J=4.4 Hz, 1H), 7.00˜7.87 (m,4H)

Preparation Example 114 Preparation of1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)-butane

The substantially same method as described in Preparation Example 69 wasconducted, except that 1-(2-iodophenyl)-(S,S)-1,2-butanediol(Preparation example 68) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14) toobtain the title compound (3.3 g, yield 90˜120%).

¹H NMR (400 MHz, CDCl₃) δ−0.053 (s, 9H), 0.044 (s, 9H), 1.04 (t, J=7.6Hz, 3H), 1.60˜1.71 (m, 2H), 3.71˜3.76 (m, 1H), 4.87 (d, J=4.8 Hz, 1H),7.01˜7.87 (m, 4H)

Example 1 Preparation of1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate(1)

To a stirred solution of crude1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(preparation example 69, 104 g, 0.31 mol) in toluene (670 mL) was addedby Chlorosulfonyl isocynate (62.5 mL, 0.71 mol) at 0° C. The reactionmixture was stirred for 2 hr. The reaction mixture was quenched with icewater and then was stirred by additional cold H₂O (500 mL) for 2 hr.After separation of organic layer, the aqueous was adjusted pH2˜3 withsat. NaHCO₃ (400 mL) and extracted with EtOAc (300 mL ×3). The EtOAclayer was washed with sat. NaHCO₃ (500 mL) and H₂O (500 mL). The organicphase was treated with Charcol for 1.5 hr. The organic phase wasfiltered with Cellite, dried over MgSO₄. Filterion and concentrationunder vacuum provided the title compound of white solid (yield 85% (71.1g), ee=99.9% MP=83˜84° C., [α]_(D)=+57.8 (c=0.25, MeOH))

¹H NMR (400 MHz, CDCl₃) δ1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68(br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H),7.55 (dd, J=1.6, J=7.8, 1H)

¹³C NMR (100 MHz, CDCl₃) δ16.4, 73.1, 75.0, 127.0, 128.4, 129.1, 129.5,132.7, 138.0, 156.6

Example 2 Preparation of1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate(2)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation example 70) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (5.7 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68(br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H),7.55 (dd, J=1.6, J=7.8, 1H)

Example 3 Preparation of1-(2-chlorophenyl)-1-hydroxypropyl-2-carbamate(3)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 71) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (3.8 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68(br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H),7.55 (dd, J=1.6, J=7.8, 1H)

Example 4 Preparation of1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-carbamate(4)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-(S,R)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation example 72) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.4 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68(br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H),7.55 (dd, J=1.6, J=7.8, 1H)

Example 5 Preparation of1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(S)-2-carbamate(5)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-(R,S)-1,2-(Bis-trimethylsilanyloxy)propane (Preparation example 73) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.3 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.24 (d, J=6.4, 3H), 2.91 (d, J=4.8, 1H), 4.68(br s, 2H), 5.06˜5.09 (m, 1H), 5.18˜5.21 (m, 1H), 7.23˜7.39 (m, 3H),7.55 (dd, J=1.6, J=7.8, 1H)

Example 6 Preparation of1-(2-chlorophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate(6)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation example 74) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.6 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.96 (t, J=7.4 Hz, 3H), 1.57˜1.73 (m, 2H), 3.01(d, J=5.6 Hz, 1H), 4.74 (br s, 2H), 4.95 (dt, J=7.2, 8.8 Hz, 1H), 5.23(t, J=5.6 Hz, 1H), 7.22˜7.54 (m, 4H)

Example 7 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxybutyl-(R)-2-carbamate(7)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 75) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.5 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.94 (t, J=7.4 Hz, 3H), 1.53˜1.73 (m, 2H),2.92 (s, 1H), 4.78 (br s, 2H), 4.91˜4.96 (m, 1H), 5.22 (d, J=5.5 Hz,1H), 7.20˜7.54 (m, 4H)

Example 8 Synthesis of 1-(2-chlorophenyl)-1-hydroxybutyl-2-carbamate(8)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 76) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.9 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.97 (t, J=7 Hz, 3H), 1.58˜1.74 (m, 2H), 2.94(d, J=6 Hz, 1H), 4.69 (br s, 2H), 4.94˜4.99 (m, 1H), 5.24 (t, J=6 Hz,1H), 7.23˜7.56 (m, 4H)

Example 9 Synthesis of1-(2-chlorophenyl)-(S)-1-hydroxy-3-methyl-butyl-(S)-2-carbamate(9)

The substantially same method as described in Example 1 was conducted,except that1-(2-chlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 77) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.7 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.01 (d, J=6.4 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H),2.06 (m, 1H), 2.75 (d, J=6.8 Hz, 1H), 4.58 (br s, 2H), 4.85˜4.88 (m,1H), 5.34˜5.37 (m, 1H), 7.22˜7.33 (m, 2H), 7.35˜7.37 (m, 1H), 7.51˜7.53(m, 1H)

Example 10 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxy-3-methyl-butyl-(R)-2-carbamate(10)

The substantially same method as described in Example 1 was conducted,except that1-(2-chlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 78) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.6 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.01 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H),2.06 (m, 1H), 2.73 (d, J=6.8 Hz, 1H), 4.57 (br s, 2H), 4.85˜4.88 (m,1H), 5.34˜5.37 (m, 1H), 7.24˜7.30 (m, 2H), 7.35˜7.37 (m, 1H), 7.51˜7.53(m, 1H)

Example 11 Synthesis of1-(2-chlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate(11)

The substantially same method as described in Example 1 was conducted,except that1-(2-chlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 79) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.7 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (d, J=6.4 Hz, 3H), 1.09 (d, J=6.4 Hz, 3H),2.08 (m, 1H), 2.76 (d, J=6.0 Hz, 1H), 4.59 (br s, 2H), 4.87 (dd, J=7.2Hz, 4.4 Hz, 1H), 5.36 (t, J=4.6, 1H), 7.23˜7.54 (m, 4H)

Example 12 Synthesis of1-(2-chlorophenyl)-(S)-1-hydroxyhexyl-(S)-2-carbamate(12)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)hexane(Preparation Example 80) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.3 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.88 (t, J=7 Hz, 3H), 1.33˜1.42 (m, 4H),1.53˜1.71 (m, 2H), 2.89 (d, J=5.6 Hz, 1H) 4.64 (br s, 2H), 5.04 (dt,J=5.0, 9.0 Hz, 1H), 5.20 (t, J=5.6 Hz, 1H), 7.23˜7.55 (m, 4H)

Example 13 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxyhexyl-(R)-2-carbamate(13)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)hexane(Preparation Example 81) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.2 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.89 (dd, J=5 Hz, 3H), 1.28˜1.43 (m, 4H),1.52˜1.58 (m, 1H), 1.65˜1.72 (m, 1H), 2.90 (d, J=6 Hz, 1H), 4.64 (br s,2H), 5.01˜5.06 (m, 1H), 5.22 (t, J=6 Hz, 1H), 7.22˜7.56 (m, 4H)

Example 14 Synthesis of1-(2-chlorophenyl)-1-hydroxyhexyl-2-carbamate(14)

The substantially same method as described in Example 1 was conducted,except that 1-(2-chlorophenyl)-1,2-(Bis-trimethylsilanyloxy)hexane(Preparation Example 82) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.1 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ 0.88 (dd, J=5 Hz, 3H), 1.31˜1.43 (m, 4H),1.63˜1.70 (m, 1H), 1.52˜1.60 (m, 1H), 3.06 (d, J=6 Hz, 1H), 4.75 (br s,2H), 5.00˜5.05 (m, 1H), 5.21 (t, J=6 Hz, 1H), 7.22˜7.55 (m, 4H)

Example 15 Synthesis of1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-methylcarbamate(15)

1-(2-chlorophenyl)-(S,S)-1,2-propanediol (2.4 g) obtained in PreparationExample 14, tetrahydrofuran (THF, 12 ml), and carbonyldiimidazole (CDI,3.12 g) were put into a flask and stirred at the room temperature. Afterapproximately 3 hours, methylamine solution(CH₃NH₂, 4 ml (33% in EtOH))was added thereto. When the reaction was completed, the obtained productwas washed with 1M HCl solution and ethylacetate (EA). The separatedorganic layer was dehydrated with anhydrous magnesium sulfate (MgSO₄),filtrated, and concented under reduced pressure. The concentratedresidue was purified by a silica gel column chromatography, to obtainthe title compound (1.6 g, yield 51%).

¹H NMR (400 MHz, CDCl₃) δ1.03˜1.25 (m, 3H), 2.76 (s, 3H), 3.34 (s, 1H),4.80 (br s 1H), 5.04 (t, J=12.5 Hz, 1H), 5.14 (s, 1H), 7.20˜7.53 (m, 4H)

Example 16 Synthesis of1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-propylcarbamate(16)

The substantially same method as described in Example 15 was conducted,except that propylamine was used instead of methylamine solution (CH₃NH₂in EtOH), to obtain the title compound (0.79 g, yield 25%).

¹H NMR (400 MHz, CDCl₃) δ0.90 (t, J=6.8 Hz, 3H), 1.20 (d, J=5.96 Hz,3H), 1.49 (dd, J=14.2 Hz, 2H), 3.11 (d, J=6.28 Hz, 2H), 3.34 (s, 1H),4.84 (br s, 1H), 5.05 (t, J=5.88 Hz, 1H), 5.14 (s, 1H), 7.22˜7.53 (m,4H)

Example 17 Synthesis of1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-N-isopropylcarbamate(17)

The substantially same method as described in Example 15 was conducted,except that isopropylamine was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (1.5 g, yield 41%).

¹H NMR (400 MHz, CDCl₃) δ1.14 (dd, J=6.5 Hz, 6H), 1.19 (d, J=6.4 Hz,3H), 3.21 (s, 1H), 3.73˜3.82 (m, 1H), 4.59 (br s, 1H), 5.01˜5.07 (m,1H), 5.14 (t, J=5.8 Hz, 1H), 7.20˜7.53 (m, 4H)

Example 18 Synthesis of1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-N-cyclopropylcarbamate(18)

The substantially same method as described in Example 15 was conducted,except that cyclopropylamine was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (2.2 g, yield 43%).

¹H NMR (400 MHz, CDCl₃) δ0.50˜0.56 (m, 2H), 0.74 (d, J=7.21 Hz, 2H),1.25 (s, 3H), 2.56˜2.61 (m, 1H), 3.72 (s, 1H), 4.98 (br s, 1H),5.05˜5.11 (m, 1H), 7.16 (s, 1H), 7.23˜7.54 (m, 4H)

Example 19 Synthesis of1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(R)-2-N-cyclohexyl carbamate(19)

The substantially same method as described in Example 15 was conducted,except that cyclohexylamine was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (1.1 g, yield 26%).

¹H NMR (400 MHz, CDCl₃) δ1.06˜1.40 (m, 7H), 1.56˜1.61 (m, 2H), 1.69˜1.71(m, 2H), 1.87˜1.94 (m, 2H), 3.19 (d, J=4.32 Hz, 1H), 3.45 (s, 1H), 4.64(br s 1H), 5.02˜5.07 (m, 1H), 5.14 (t, J=6.08 Hz, 1H) 7.20˜7.53 (m, 4H)

Example 20 Synthesis of1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-benzyl carbamate(20)

The substantially same method as described in Example 15 was conducted,except that benzylamine was used instead of methylamine solution (CH₃NH₂in EtOH), to obtain the title compound (1.2 g, yield 18%).

¹H NMR (400 MHz, CDCl₃) δ 1.27 (d, J=10 Hz, 3H), 3.12 (d, J=5 Hz, 1H),4.37 (d, J=6 Hz, 2H), 5.12˜5.19 (m, 3H), 7.15˜7.56 (m, 9H)

Example 21 Synthesis of1-(2-chlorophenyl)-(S)-1-hydroxypropyl-(S)-2-N-bicyclo[2,2,1]heptanescarbamate(21)

The substantially same method as described in Example 15 was conducted,except that 2-aminonorbornane was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (1.7 g, yield 32%).

¹H NMR (400 MHz, CDCl₃) δ1.08˜1.35 (m, 9H), 1.65 (br s, 1H), 1.75˜1.71(m, 1H), 2.14˜2.24 (m, 1H), 2.27˜2.30 (m, 1H), 3.23˜3.29 (m, 1H),3.47˜3.52 (m, 1H), 4.67 (br s, 1H), 5.01˜5.09 (m, 1H), 5.12˜5.18 (m,1H), 7.22˜7.55 (m, 4H)

Example 22 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-methylcarbamate(22)

The substantially same method as described in Example 15 was conducted,except that 1-(2-chlorophenyl)-(R,R)-1,2-propanediol (Preparationexample 15) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (3.36 g, yield60%).

¹H NMR (400 MHz, CDCl₃) δ 1.20 (d, J=6.8 Hz, 3H), 2.80 (d, J=4.8 Hz,3H), 3.20 (d, J=4.4 Hz, 1H), 4.75 (br s, 1H), 5.03˜5.09 (m, 1H),5.14˜5.17 (m, 1H), 7.22˜7.55 (m, 4H)

Example 23 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-propylcarbamate(23)

The substantially same method as described in Example 22 was conducted,except that propylamine was used instead of methylamine solution (CH₃NH₂in EtOH), to obtain the title compound (3.1 g, yield 53%).

¹H NMR (400 MHz, CDCl₃) δ0.92 (t, J=7.6 Hz, 3H), 1.21 (d, J=6.4 Hz, 3H),1.51 (m, 2H), 3.09˜3.14 (m, 2H), 3.28 (d, J=4.4 Hz, 1H), 4.82 (br s,1H), 5.03˜5.09 (m, 1H), 5.14˜5.17 (m, 1H), 7.22˜7.55 (m. 4H)

Example 24 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-isopropylcarbamate(24)

The substantially same method as described in Example 22 was conducted,except that isopropylamine was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (0.16 g, yield 27%).

¹H NMR (400 MHz, CDCl₃) δ0.88˜1.16 (m, 6H), 1.19˜1.26 (m, 3H), 3.34 (s,1H), 3.71˜3.78 (m, 1H), 4.62 (br s, 1H), 5.03 (t, J=5.8 Hz, 1H), 5.13(d, J=4.9 Hz, 1H), 7.20˜7.53 (m, 4H)

Example 25 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-cyclopropylcarbamate(25)

The substantially same method as described in Example 22 was conducted,except that cyclopropylamine was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (3.7 g, yield 60%).

¹H NMR (400 MHz, CDCl₃) δ0.49˜0.54 (m, 2H), 0.74 (d, J=7.2 Hz, 2H), 1.22(s, 3H), 2.55˜2.60 (m, 1H), 3.16 (s, 1H), 5.00 (s, 1H), 5.04˜5.11 (m,1H), 5.16 (s, 1H), 7.23˜7.54 (m, 4H)

Example 26 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-cyclohexyl carbamate(26)

The substantially same method as described in Example 22 was conducted,except that cyclohexylamine was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (1.9 g, yield 28%).

¹H NMR (400 MHz, CDCl₃) δ1.05˜1.38 (m, 8H), 1.58˜1.70 (m, 3H), 1.85˜1.95(m, 2H), 3.39˜3.47 (m, 1H), 3.56 (s, 1H), 4.79 (br s, 1H), 5.01˜5.07 (m,1H), 5.14 (t, J=5.2 Hz, 1H), 7.20˜7.54 (m, 4H)

Example 27 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-benzylcarbamate(27)

The substantially same method as described in Example 22 was conducted,except that benzylamine was used instead of methylamine solution (CH₃NH₂in EtOH), to obtain the title compound (0.52 g, yield 19%).

¹H NMR (400 MHz, CDCl₃) δ1.25 (d, J=6 Hz, 3H), 1.64 (s, 1H), 3.13 (d,J=4.4 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H), 5.12˜5.19 (m, 2H), 7.23˜7.55 (m,9H)

Example 28 Synthesis of1-(2-chlorophenyl)-(R)-1-hydroxypropyl-(R)-2-N-bicyclo[2,2,1]heptanecarbamate(28)

The substantially same method as described in Example 22 was conducted,except that 2-aminonorbornane was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (1.7 g, yield 20˜50%).

¹H NMR (400 MHz, CDCl₃) δ1.08˜1.35 (m, 9H), 1.65 (br s, 1H), 1.75˜1.71(m, 1H), 2.14˜2.24 (m, 1H), 2.27˜2.30 (m, 1H), 3.23˜3.29 (m, 1H),3.47˜3.52 (m, 1H), 4.67 (br s, 1H), 5.01˜5.09 (m, 1H), 5.12˜5.18 (m,1H), 7.22˜7.55 (m, 4H)

Example 29 Synthesis of1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate(29)

The substantially same method as described in Example 15 was conducted,except that 1-(2-chlorophenyl)-1,2-propanediol (Preparation example 16)was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (2.6 g, yield45%).

¹H NMR (400 MHz, CDCl₃) δ 1.21 (d, J=6 Hz, 3H), 2.81 (d, J=5 Hz, 3H),3.14 (d, J=4 Hz, 1H), 4.72 (br s, 1H), 5.07 (dd, J=6 Hz, 1H), 5.16 (t,J=6 Hz, 1H), 7.22˜7.56 (m, 4H)

Example 30 Synthesis of1-(2-chlorophenyl)-1-hydroxypropyl-2-N-propylcarbamate(30)

The substantially same method as described in Example 29 was conducted,except that propylamine was used instead of methylamine solution (CH₃NH₂in EtOH), to obtain the title compound (1.0 g, yield 17%).

¹H NMR (400 MHz, CDCl₃) δ 0.92 (t, J=7 Hz, 3H), 1.21 (d, J=6 Hz, 3H),1.53 (dd, J=7 Hz, 2H), 3.13 (dd, J=7 Hz, 2H), 3.28 (d, 1H), 4.82 (S,1H), 5.06 (dd, J=7 Hz, 1H), 5.16 (t, J=5 Hz, 1H), 7.21˜7.56 (m, 4H)

Example 31 Synthesis of1-(2-chlorophenyl)-1-hydroxypropyl-2-N-isopropylcarbamate(31)

The substantially same method as described in Example 29 was conducted,except that isopropylamine was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (0.54 g, yield 16%).

¹H NMR (400 MHz, CDCl₃) δ 1.16 (dd, J=6 Hz, 6H), 1.21 (d, J=6 Hz, 3H),3.23 (d, J=6 Hz, 1H), 3.75˜3.84 (m, 1H), 4.61 (br s, 1H), 5.06 (t, J=6Hz, 1H), 5.16 (t, J=6 Hz, 1H), 7.22˜7.56 (m, 4H)

Example 32 Synthesis of1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclopropylcarbamate(32)

The substantially same method as described in Example 29 was conducted,except that cyclopropylamine was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (1.0 g, yield 17%).

¹H NMR (400 MHz, CDCl₃) δ 0.50 (t, J=6 Hz, 2H), 0.77 (t, J=3 Hz, 2H),1.12 (d, J=7 Hz, 3H), 2.53˜2.59 (m, 1H), 3.22 (d, J=4 Hz, 1H), 5.08 (dd,J=6 Hz, 1H), 5.15 (S, 1H), 7.22˜7.55 (m, 4H)

Example 33 Synthesis of1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclohexylcarbamate(33)

The substantially same method as described in Example 29 was conducted,except that cyclohexylamine was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (2.2 g, yield 33%).

¹H NMR (400 MHz, CDCl₃) δ 1.07˜1.17 (m, 3H), 1.21 (d, J=6 Hz, 3H),1.29˜1.42 (m, 3H), 1.72 (dd, J=6 Hz, 2H), 1.92 (dd, J=6 Hz, 2H), 3.26(d, J=4 Hz, 1H), 3.46 (t, J=4 Hz, 1H), 4.68 (d, J=6 Hz, 1H), 5.07 (dd,J=6 Hz, 1H), 5.16 (t, J=6 Hz, 1H), 7.22˜7.55 (m, 4H)

Example 34 Synthesis of1-(2-chlorophenyl)-1-hydroxypropyl-2-N-benzylcarbamate(34)

The substantially same method as described in Example 29 was conducted,except that benzylamine was used instead of methylamine solution (CH₃NH₂in EtOH), to obtain the title compound (1.3 g, yield 19%).

¹H NMR (400 MHz, CDCl₃) δ 1.25 (d, J=6 Hz, 3H), 3.16 (d, J=4 Hz, 1H),4.36 (d, J=6 Hz, 2H), 5.14 (dd, J=6 Hz, 3H), 7.23˜7.56 (m, 9H), yield:19% (1.3 g)

Example 35 Synthesis of1-(2-chlorophenyl)-1-hydroxypropyl-2-N-bicyclo[2,2,1]heptanecarbamate(35)

The substantially same method as described in Example 29 was conducted,except that 2-aminonorbornane was used instead of methylamine solution(CH₃NH₂ in EtOH), to obtain the title compound (1.7 g, yield 20˜50%).

¹H NMR (400 MHz, CDCl₃) δ1.08˜1.35 (m, 9H), 1.65 (br s, 1H), 1.75˜1.71(m, 1H), 2.14˜2.24 (m, 1H), 2.27˜2.30 (m, 1H), 3.23˜3.29 (m, 1H),3.47˜3.52 (m, 1H), 4.67 (br s, 1H), 5.01˜5.09 (m, 1H), 5.12˜5.18 (m,1H), 7.22˜7.55 (m, 4H)

Example 36 Synthesis of1-(2,4-dichlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate(36)

The substantially same method as described in Example 1 was conducted,except that1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 83) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.8 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.22 (d, J=6.4 Hz, 3H), 4.16 (br t, 1H) 4.96(br t, 3H), 5.07 (t, J=4.8 Hz, 1H), 7.23˜7.52 (m, 3H)

Example 37 Synthesis of1-(2,6-dichlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate(37)

The substantially same method as described in Example 1 was conducted,except that1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 84) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.6 g, yield60˜90%)

Example 38 Synthesis of1-(2,3-dichlorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate(38)

The substantially same method as described in Example 1 was conducted,except that1-(2,3-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 85) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.4 g, yield60˜90%)

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H),4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22(m, 3H),

Example 39 Synthesis of1-(2,4-dichlorophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate(39)

The substantially same method as described in Example 1 was conducted,except that1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 86) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.3 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.96 (t, J=7.4 Hz, 3H), 1.58˜1.74 (m, 2H), 2.98(d, J=5.6 Hz, 1H) 4.68 (br s, 2H), 5.59 (dt, J=5.2, 8.8 Hz, 1H), 5.19(t, J=5.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 40 Synthesis of1-(2,6-dichlorophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate(40)

The substantially same method as described in Example 1 was conducted,except that1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 87) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.7 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.92 (t, J=7.4 Hz, 3H), 1.30˜1.38 (m, 1H),1.57˜1.64 (m, 1H), 3.74 (d, J=9.2 Hz, 1H), 4.80 (br s, 2H), 5.40˜5.50(m, 2H), 7.17˜7.34 (m, 3H)

Example 41 Synthesis of1-(2,4-dichlorophenyl)-(S)-1-hydroxy-3-methyl-butyl-(S)-2-carbamate(41)

The substantially same method as described in Example 1 was conducted,except that1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 88) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.9 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (1, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m,1H), 7.30˜7.50 (m, 3H)

Example 42 Synthesis of1-(2,6-dichlorophenyl)-(S)-1-hydroxy-3-methyl-butyl-(S)-2-carbamate(42)

The substantially same method as described in Example 1 was conducted,except that1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 89) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.4 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m,1H), 7.16˜7.33 (m, 3H)

Example 43 Synthesis of1-(2,4-dichlorophenyl)-(S)-1-hydroxyhexyl-(S)-2-carbamate(43)

The substantially same method as described in Example 1 was conducted,except that1-(2,4-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)hexane(Preparation Example 90) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.2 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.89 (t, J=3.6 Hz, 3H), 1.28˜1.42 (m, 4H),1.52˜1.59 (m, 1H), 1.64˜1.71 (m, 1H), 2.98 (d, J=5.6 Hz, 1H), 4.67 (brs, 2H), 4.96˜5.00 (m, 1H), 5.17 (t, J=5.6 Hz, 1H), 7.30˜7.49 (m 3H)

Example 44 Synthesis of1-(2,6-dichlorophenyl)-(S)-1-hydroxyhexyl-(S)-2-carbamate(44)

The substantially same method as described in Example 1 was conducted,except that1-(2,6-dichlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)hexane(Preparation Example 91) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.1 g, yield60˜90%)

¹H NMR (400 MHz, CDCl₃) δ0.84 (t, J=7.0 Hz, 3H), 1.20˜1.35 (m, 4H),1.36˜1.41 (m, 1H), 1.59˜1.63 (m, 1H), 3.71 (d, J=10.0 Hz, 1H), 4.74 (brs, 2H), 5.40˜5.44 (m, 1H), 5.52˜5.57 (m, 1H), 7.17˜7.35 (m, 3H)

Example 45 Synthesis of1-(2,4-dichlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate(45)

The substantially same method as described in Example 1 was conducted,except that1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 92) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.2 g, yield60˜90%),

¹H NMR (400 MHz, CDCl₃) δ1.22 (d, J=6.4 Hz, 3H), 4.16 (br t, 1H) 4.96(br t, 3H), 5.07 (t, J=4.8 Hz, 1H), 7.23˜7.52 (m, 3H)

Example 46 Synthesis of1-(2,6-dichlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate(46)

The substantially same method as described in Example 1 was conducted,except that1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 93) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.7 g, yield60˜90%),

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H),4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22(m, 3H),

Example 47 Synthesis of1-(2,3-dichlorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate(47)

The substantially same method as described in Example 1 was conducted,except that1-(2,3-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 94) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.0 g, yield60˜90%)

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H),4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22(m, 3H),

Example 48 Synthesis of1-(2,4-dichlorophenyl)-(R)-1-hydroxybutyl-(R)-2-carbamate(48)

The substantially same method as described in Example 1 was conducted,except that1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 95) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.3 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.96 (t, J=7.4 Hz, 3H), 1.58˜1.74 (m, 2H), 2.98(d, J=5.6 Hz, 1H) 4.68 (br s, 2H), 5.59 (dt, J=5.2, 8.8 Hz, 1H), 5.19(t, J=5.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 49 Synthesis of1-(2,6-dichlorophenyl)-(R)-1-hydroxybutyl-(R)-2-carbamate(49)

The substantially same method as described in Example 1 was conducted,except that1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 96) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.5 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.92 (t, J=7.4 Hz, 3H), 1.30˜1.38 (m, 1H),1.57˜1.64 (m, 1H), 3.74 (d, J=9.2 Hz, 1H), 4.80 (br s, 2H), 5.40˜5.50(m, 2H), 7.17˜7.34 (m, 3H)

Example 50 Synthesis of1-(2,4-dichlorophenyl)-(R)-1-hydroxy-3-methyl-butyl-(R)-2-carbamate(50)

The substantially same method as described in Example 1 was conducted,except that1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 97) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.8 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (1, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m,1H), 7.30˜7.50 (m, 3H)

Example 51 Synthesis of1-(2,6-dichlorophenyl)-(R)-1-hydroxy-3-methyl-butyl-(R)-2-carbamate(51)

The substantially same method as described in Example 1 was conducted,except that1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 98) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.6 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (1, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m,1H), 7.16˜7.33 (m, 3H)

Example 52 Synthesis of1-(2,4-dichlorophenyl)-(R)-1-hydroxyhexyl-(R)-2-carbamate(52)

The substantially same method as described in Example 1 was conducted,except that1-(2,4-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)hexane(Preparation Example 99) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.5 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.89 (t, J=3.6 Hz, 3H), 1.28˜1.42 (m, 4H),1.52˜1.59 (m, 1H), 1.64˜1.71 (m, 1H), 2.98 (d, J=5.6 Hz, 1H), 4.67 (brs, 2H), 4.96˜5.00 (m, 1H), 5.17 (t, J=5.6 Hz, 1H), 7.30˜7.49 (m, 3H)

Example 53 Synthesis of1-(2,6-dichlorophenyl)-(R)-1-hydroxyhexyl-(R)-2-carbamate(53)

The substantially same method as described in Example 1 was conducted,except that1-(2,6-dichlorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)hexane(Preparation Example 100) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.4 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.84 (t, J=7.0 Hz, 3H), 1.20˜1.35 (m, 4H),1.36˜1.41 (m, 1H), 1.59˜1.63 (m, 1H), 3.71 (d, J=10.0 Hz, 1H), 4.74 (brs, 2H), 5.40˜5.44 (m, 1H), 5.52˜5.57 (m, 1H), 7.17˜7.35 (m, 3H)

Example 54 Synthesis of1-(2,4-dichlorophenyl)-1-hydroxypropyl-2-carbamate(54)

The substantially same method as described in Example 1 was conducted,except that 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 101) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.7 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.22 (d, J=6.4 Hz, 3H), 4.16 (br t, 1H) 4.96(br t, 3H), 5.07 (t, J=4.8 Hz, 1H), 7.23˜7.52 (m, 3H)

Example 55 Synthesis of1-(2,6-dichlorophenyl)-1-hydroxypropyl-2-carbamate(55)

The substantially same method as described in Example 1 was conducted,except that 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 102) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.4 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H),4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22(m, 3H),

Example 56 Synthesis of1-(2,3-dichlorophenyl)-1-hydroxypropyl-2-carbamate(56)

The substantially same method as described in Example 1 was conducted,except that 1-(2,3-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 103) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.6 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H),4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22(m, 3H),

Example 57 Synthesis of1-(2,4-dichlorophenyl)-1-hydroxybutyl-2-carbamate(57)

The substantially same method as described in Example 1 was conducted,except that 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 104) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.7 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.96 (t, J=7.4 Hz, 3H), 1.58˜1.74 (m, 2H), 2.98(d, J=5.6 Hz, 1H) 4.68 (br s, 2H), 5.59 (dt, J=5.2, 8.8 Hz, 1H), 5.19(t, J=5.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 58 Synthesis of1-(2,6-dichlorophenyl)-1-hydroxybutyl-2-carbamate(58)

The substantially same method as described in Example 1 was conducted,except that 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 105) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.4 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.92 (t, J=7.4 Hz, 3H), 1.30˜1.38 (m, 1H),1.57˜1.64 (m, 1H), 3.74 (d, J=9.2 Hz, 1H), 4.80 (br s, 2H), 5.40˜5.50(m, 2H), 7.17˜7.34 (m, 3H)

Example 59 Synthesis of1-(2,4-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate(59)

The substantially same method as described in Example 1 was conducted,except that1-(2,4-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 106) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.9 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m,1H), 7.30˜7.50 (m, 3H)

Example 60 Synthesis of1-(2,6-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate(60)

The substantially same method as described in Example 1 was conducted,except that1-(2,6-dichlorophenyl)-3-methyl-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 107) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.7 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.85 (br s, 2H), 5.40˜5.43 (m, 1H), 5.49˜5.54 (m,1H), 7.16˜7.33 (m, 3H)

Example 61 Synthesis of1-(2,4-dichlorophenyl)-1-hydroxyhexyl-2-carbamate(61)

The substantially same method as described in Example 1 was conducted,except that 1-(2,4-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)hexane(Preparation Example 108) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.6 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.89 (t, J=3.6 Hz, 3H), 1.28˜1.42 (m, 4H),1.52˜1.59 (m, 1H), 1.64˜1.71 (m, 1H), 2.98 (d, J=5.6 Hz, 1H), 4.67 (brs, 2H), 4.96˜5.00 (m, 1H), 5.17 (t, J=5.6 Hz, 1H), 7.30˜7.49 (m, 3H)

Example 62 Synthesis of1-(2,6-dichlorophenyl)-1-hydroxyhexyl-2-carbamate(62)

The substantially same method as described in Example 1 was conducted,except that 1-(2,6-dichlorophenyl)-1,2-(Bis-trimethylsilanyloxy)hexane(Preparation Example 109) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.5 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ0.84 (t, J=7.0 Hz, 3H), 1.20˜1.35 (m, 4H),1.36˜1.41 (m, 1H), 1.59˜1.63 (m, 1H), 3.71 (d, J=10.0 Hz, 1H), 4.74 (brs, 2H), 5.40˜5.44 (m, 1H), 5.52˜5.57 (m, 1H), 7.17˜7.35 (m, 3H)

Example 63 Synthesis of1-(2-fluorophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate(63)

The substantially same method as described in Example 1 was conducted,except that1-(2-fluorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 110) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.8 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.19 (d, J=5.2 Hz, 3H), 2.93 (d, J=4.4 Hz, 1H),4.71 (br s, 2H), 4.99˜5.06 (m, H), 7.04˜7.48 (m, 4H)

Example 64 Synthesis of1-(2-fluorophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate(64)

The substantially same method as described in Example 1 was conducted,except that1-(2-fluorophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 111) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.6 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.19 (d, J=5.2 Hz, 3H), 2.93 (d, J=4.4 Hz, 1H),4.71 (br s, 2H), 4.99˜5.06 (m, H), 7.04˜7.48 (m, 4H)

Example 65 Synthesis of1-(2-iodophenyl)-(S)-1-hydroxypropyl-(S)-2-carbamate(65)

The substantially same method as described in Example 1 was conducted,except that 1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 112) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.2 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.27 (d, J=6.4 Hz, 3H), 3.09 (br s, 1H), 4.83(br s, 2H), 5.00˜5.10 (m, 2H), 7.00˜7.76 (m, 4H)

Example 66 Synthesis of1-(2-iodophenyl)-(R)-1-hydroxypropyl-(R)-2-carbamate(66)

The substantially same method as described in Example 1 was conducted,except that 1-(2-iodophenyl)-(R,R)-1,2-(Bis-trimethylsilanyloxy)propane(Preparation Example 113) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (1.7 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.27 (d, J=6.4 Hz, 3H), 2.95 (d, J=3.6 Hz, 1H),4.73 (br s, 2H), 5.01˜5.11 (m, 2H), 7.01˜7.86 (m, 4H)

Example 67 Synthesis of1-(2-iodophenyl)-(S)-1-hydroxybutyl-(S)-2-carbamate(67)

The substantially same method as described in Example 1 was conducted,except that 1-(2-iodophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy)butane(Preparation Example 114) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-(Bis-trimethylsilanyloxy) propane(Preparation example 69) to obtain the title compound (2.1 g, yield60˜90%).

¹H NMR (400 MHz, CDCl₃) δ1.27 (d, J=6.4 Hz, 3H), 3.09 (br s, 1H), 4.83(br s, 2H), 5.00˜5.10 (m, 2H), 7.00˜7.76 (m, 4H)

Example 68 Synthesis of1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-carbamate(68)

1-(2-chlorophenyl)-(S,S)-1,2-propanediol (2.33 g, Preparation example14) obtained in Preparation Example 14, tetrahydrofuran (THF, 12 ml),and carbonyldiimidazole (CDI, 3.04 g) were put into a flask and stirredat the room temperature. After approximately 3 hours, ammonia solution(NH₄OH, 4 ml) was added thereto. When the reaction was completed, theobtained product was washed with 1M HCl solution and ethylacetate (EA).The separated organic layer was dehydrated with anhydrous magnesiumsulfate (MgSO₄), filtrated, and concented under reduced pressure. Theconcentrated residue was purified by a silica gel column chromatography,to obtain the title compound (0.28 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.24 (d, J=6.8 Hz, 3H), 2.13 (d, J=4.4 Hz, 1H),4.12˜4.16 (m, 1H), 4.85 (br s, 2H), 5.98 (d, J=5.6 Hz, 1H), 7.24˜7.43(m, 4H)

Example 69 Synthesis of1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-carbamate(69)

The substantially same method as described in Example 68 was conducted,except that 1-(2-chlorophenyl)-(R,R)-1,2-propanediol (PreparationExample 15) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14) to obtain the title compound (0.77 g, yield16%).

¹H NMR (400 MHz, CDCl₃) δ1.24 (d, J=6.4 Hz, 3H), 2.04 (d, J=4.8 Hz, 1H),4.11˜4.18 (m, 1H), 4.74 (br s, 2H), 6.00 (d, J=5.6 Hz, 1H), 7.24˜7.43(m, 4H)

Example 70 Synthesis of1-(2-chlorophenyl)-2-hydroxypropyl-1-carbamate(70)

The substantially same method as described in Example 68 was conducted,except that 1-(2-chlorophenyl)-(R,R)-1,2-propanediol (PreparationExample 16) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14) to obtain the title compound (0.16 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.24 (d, J=6.4 Hz, 3H), 2.04 (d, J=4.8 Hz, 1H),4.11˜4.18 (m, 1H), 4.74 (br s, 2H), 6.00 (d, J=5.6 Hz, 1H), 7.24˜7.43(m, 4H)

Example 71 Synthesis of1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-methylcarbamate(71)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 15, toobtain the title compound (0.70 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.21 (d, J=6.4 Hz, 3H), 2.80 (d, J=4.8 Hz, 3H),3.12 (s, 1H), 4.09˜4.16 (m, 1H), 4.86 (br s, 1H), 5.99 (d, J=6.0 Hz,1H), 7.23˜7.40 (m, 4H)

Example 72 Synthesis of1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-methylcarbamate(72)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 22, toobtain the title compound (0.69 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.21 (d, J=6.4 Hz, 3H), 2.80 (d, J=4.8 Hz, 3H),3.12 (s, 1H), 4.09˜4.16 (m, 1H), 4.86 (br s, 1H), 5.99 (d, J=6.0 Hz,1H), 7.23˜7.40 (m, 4H)

Example 73 Synthesis of1-(2-chlorophenyl)-2-hydroxypropyl-1-N-methylcarbamate(73)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 29, toobtain the title compound (0.73 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.22 (d, J=6 Hz, 3H), 2.15 (d, J=4 Hz, 1H),2.81 (d, J=5 Hz, 3H), 4.12 (dd, J=6 Hz, 1H), 4.83 (br s, 1H), 6.00 (d,J=6 Hz, 1H), 7.23˜7.41 (m, 4H)

Example 74 Synthesis of1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-propylcarbamate(74)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 16, toobtain the title compound (0.15 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.91 (t, J=7 Hz, 3H), 1.22 (d, J=6 Hz, 3H),1.52 (dd, J=7 Hz, 2H), 2.23 (d, J=4 Hz, 1H), 3.09˜3.21 (m, 2H),4.09˜4.17 (m, 1H), 4.93 (s, 1H), 5.99 (d, J=6 Hz, 1H), 7.23˜7.47 (m, 4H)

Example 75 Synthesis of1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-propylcarbamate(75)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 23, toobtain the title compound (0.04 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.91 (t, J=7 Hz, 3H), 1.22 (d, J=6 Hz, 3H),1.52 (dd, J=7 Hz, 2H), 2.23 (d, J=4 Hz, 1H), 3.09˜3.21 (m, 2H),4.09˜4.17 (m, 1H), 4.93 (s, 1H), 5.99 (d, J=6 Hz, 1H), 7.23˜7.47 (m, 4H)

Example 76 Synthesis of1-(2-chlorophenyl)-2-hydroxypropyl-1-N-propylcarbamate(76)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 30, toobtain the title compound (0.15 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 0.91 (t, J=7 Hz, 3H), 1.22 (d, J=6 Hz, 3H),1.52 (dd, J=7 Hz, 2H), 2.23 (d, J=4 Hz, 1H), 3.09˜3.21 (m, 2H),4.09˜4.17 (m, 1H), 4.93 (s, 1H), 5.99 (d, J=6 Hz, 1H), 7.23˜7.47 (m, 4H)

Example 77 Synthesis of1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-isopropylcarbamate(77)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 17, toobtain the title compound (0.42 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.10 (d, J=6.0 Hz, 3H), 1.15˜1.19 (m, 6H), 2.41(s, 1H), 3.76˜4.08 (m, 1H), 4.34 (s, 1H), 4.83 (br s 1H), 5.95 (d, J=5.3Hz, 1H), 7.19˜7.39 (m, 4H)

Example 78 Synthesis of1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-isopropylcarbamate(78)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 24, toobtain the title compound (0.5 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.13 (d, J=6 Hz, 3H), 1.20 (dd, J=9.2 Hz, 6H),2.23 (s, 1H), 3.77˜3.82 (m, 1H), 4.10 (s, 1H), 4.76 (br s, 1H), 5.98 (d,J=5.6 Hz, 1H), 7.23˜7.41 (m, 4H)

Example 79 Synthesis of1-(2-chlorophenyl)-2-hydroxypropyl-1-N-isopropylcarbamate(79)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 31, toobtain the title compound (0.09 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.14 (d, J=6 Hz, 3H), 1.21 (dd, J=6 Hz, 6H),2.16 (d, J=5 Hz, 1H), 3.81 (t, J=6 Hz, 1H), 4.11 (d, J=5 Hz, 1H), 4.73(br s, 1H), 5.98 (d, J=5 Hz, 1H), 7.24˜741 (m, 4H)

Example 80 Synthesis of1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-cyclopropylcarbamate(80)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 18, toobtain the title compound (0.53 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.53˜0.60 (m, 2H), 0.74 (s, 2H), 1.21 (d, J=6.0Hz, 3H), 2.19 (s, 1H), 2.59 (s, 1H), 4.11˜4.15 (m, 1H), 5.13 (br s, 1H),5.99 (d, J=5.20 Hz, 1H), 7.23˜7.40 (m, 4H)

Example 81 Synthesis of1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-cyclopropylcarbamate(81)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 25, toobtain the title compound (0.58 g, yield 10%).

¹H NMR (400 MHz, CDCl₃) δ0.53˜0.60 (m, 2H), 0.74 (s, 2H), 1.21 (d, J=6.0Hz, 3H), 2.19 (s, 1H), 2.59 (s, 1H), 4.11˜4.15 (m, 1H), 5.13 (br s, 1H),5.99 (d, J=5.20 Hz, 1H), 7.23˜7.40 (m, 4H)

Example 82 Synthesis of1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclopropylcarbamate(82)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 32, toobtain the title compound (0.38 g, yield 14%).

¹H NMR (400 MHz, CDCl₃) δ 0.71 (s, 2H), 1.19 (d, J=6 Hz, 3H), 2.45 (S,1H), 2.57 (S, 1H), 4.08˜4.12 (m, 1H), 5.26 (s, 1H), 5.97 (d, J=4 Hz,1H), 7.22˜7.54 (m, 4H)

Example 83 Synthesis of1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-cyclohexylcarbamate(83)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 19, toobtain the title compound (0.24 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.10˜1.39 (m, 7H), 1.61 (s, 3H), 1.71˜1.74 (m,2H), 1.87 (d, J=11.2 Hz, 1H), 2.48 (d, J=10.8 Hz, 1H), 3.46 (t, J=4 Hz,1H), 4.10˜4.11 (m, 1H), 4.80 (br s 1H), 5.97 (d, J=5.6 Hz, 1H),7.23˜7.41 (m, 4H)

Example 84 Synthesis of1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-cyclohexylcarbamate(84)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 26, toobtain the title compound (0.35 g, yield 10%).

¹H NMR (400 MHz, CDCl₃) δ1.10˜1.39 (m, 7H), 1.61 (s, 3H), 1.71˜1.74 (m,2H), 1.87 (d, J=11.2 Hz, 1H), 2.48 (d, J=10.8 Hz, 1H), 3.46 (t, J=4 Hz,1H), 4.10˜4.11 (m, 1H), 4.80 (br s 1H), 5.97 (d, J=5.6 Hz, 1H),7.23˜7.41 (m, 4H)

Example 85 Synthesis of1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclohexylcarbamate(85)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 33, toobtain the title compound (0.26 g, yield 10%).

¹H NMR (400 MHz, CDCl₃) δ 1.12˜1.19 (m, 3H), 1.22 (d, J=6 Hz, 3H),1.27˜1.37 (m, 1H), 1.71 (t, J=6 Hz, 2H), 1.86˜1.88 (m, 1H), 1.97˜2.00(m, 1H), 2.18 (d, J=4 Hz, 1H), 3.47 (S, 1H), 4.12 (t, J=6 Hz, 1H), 4.78(S, 1H), 5.97 (d, J=6 Hz, 1H), 7.23˜7.40 (m, 4H)

Example 86 Synthesis of1-(2-chlorophenyl)-(S)-2-hydroxypropyl-(S)-1-N-benzylcarbamate(86)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 20, toobtain the title compound (0.19 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.23 (d, J=6 Hz, 3H), 2.16 (d, J=4 Hz, 1H),4.12 (t, J=6 Hz, 1H), 4.31˜4.44 (m, 2H), 5.22 (br S, 1H), 6.04 (d, J=6Hz, 1H), 7.27˜7.42 (m, 9H)

Example 87 Synthesis of1-(2-chlorophenyl)-(R)-2-hydroxypropyl-(R)-1-N-benzylcarbamate(87)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 27, toobtain the title compound (0.07 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ 1.23 (d, J=6 Hz, 3H), 2.16 (d, J=4 Hz, 1H),4.12 (t, J=6 Hz, 1H), 4.31˜4.44 (m, 2H), 5.22 (br S, 1H), 6.04 (d, J=6Hz, 1H), 7.27˜7.42 (m, 9H)

Example 88 Synthesis of1-(2-chlorophenyl)-2-hydroxypropyl-1-N-benzylcarbamate(88)

A regioisomer of monocarbamate was separated and purified by conductingthe silica gel column chromatography as described in Example 34, toobtain the title compound (0.21 g, yield 14%).

¹H NMR (400 MHz, CDCl₃) δ 1.23 (d, J=6 Hz, 3H), 2.16 (d, J=4 Hz, 1H),4.12 (t, J=6 Hz, 1H), 4.31˜4.44 (m, 2H), 5.22 (br S, 1H), 6.04 (d, J=6Hz, 1H), 7.27˜7.42 (m, 9H)

Example 89 Synthesis of1-(2,4-dichlorophenyl)-(S)-2-hydroxypropyl-(S)-1-carbamate(89)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-propanediol (Preparationexample 26) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.05 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H),4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.30 (d,J=8.4 Hz, 1H), 7.39 (d, J=2.0 Hz, 2H), 7.50 (dd, J=8.4 Hz, 2.0 Hz, 1H)

Example 90 Synthesis of1-(2,6-dichlorophenyl)-(S)-2-hydroxypropyl-(S)-1-carbamate(90)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-propanediol (Preparationexample 38) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.07 g, yield24%).

¹H NMR (400 MHz, CDCl₃) δ1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H),4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.25˜7.40(m, 3H)

Example 91 Synthesis of1-(2,3-dichlorophenyl)-(S)-2-hydroxypropyl-(S)-1-carbamate(91)

The substantially same method as described in Example 68 was conducted,except that 1-(2,3-dichlorophenyl)-(S,S)-1,2-propanediol (Preparationexample 57) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.08 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H),4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22(m, 3H),

Example 92 Synthesis of1-(2,4-dichlorophenyl)-(S)-2-hydroxybutyl-(S)-1-carbamate(92)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-butanediol (Preparationexample 29) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.07 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m, 1H),1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d,J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.30˜7.50 (m, 3H)

Example 93 Synthesis of1-(2,6-dichlorophenyl)-(S)-2-hydroxybutyl-(S)-1-carbamate(93)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-butanediol (Preparationexample 41) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.11 g, yield29%).

¹H NMR (400 MHz, CDCl₃) δ0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m, 1H),1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d,J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.25˜7.40 (m, 3H)

Example 94 Synthesis of1-(2,4-dichlorophenyl)-(S)-2-hydroxy-3-methyl-butyl-(S)-1-carbamate(94)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol(Preparation example 32) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), toobtain the title compound (0.01 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (1, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42(br s, 2H), 7.30˜7.50 (m, 3H)

Example 95 Synthesis of1-(2,6-dichlorophenyl)-(S)-2-hydroxy-3-methyl-butyl-(S)-1-carbamate(95)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-3-methyl-(S,S)-1,2-butanediol(Preparation example 44) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), toobtain the title compound (0.03 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (1, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42(br s, 2H), 7.25˜7.40 (m, 3H)

Example 96 Synthesis of1-(2,4-dichlorophenyl)-(S)-2-hydroxyhexyl-(S)-1-carbamate(96)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-(S,S)-1,2-hexanediol (Preparationexample 35) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.21 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.85 (t, J=7.2 Hz, 3H), 1.18˜1.33 (m, 4H),1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (brs, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 97 Synthesis of1-(2,6-dichlorophenyl)-(S)-2-hydroxyhexyl-(S)-1-carbamate(97)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-(S,S)-1,2-hexanediol (Preparationexample 47) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.06 g, yield29%).

¹H NMR (400 MHz, CDCl₃) δ0.85 (t, J=7.2 Hz, 3H), 1.18˜1.33 (m, 4H),1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (brs, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.16˜7.34 (m, 3H)

Example 98 Synthesis of1-(2,4-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-1-carbamate(98)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-propanediol (Preparationexample 27) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.04 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H),4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.30˜7.50(m, 3H)

Example 99 Synthesis of1-(2,6-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-1-carbamate(99)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-propanediol (Preparationexample 39) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.09 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H),4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.25˜7.40(m, 3H)

Example 100 Synthesis of1-(2,3-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-1-carbamate(100)

The substantially same method as described in Example 68 was conducted,except that 1-(2,3-dichlorophenyl)-(R,R)-1,2-propanediol (Preparationexample 58) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.25 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H),4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22(m, 3H),

Example 101 Synthesis of1-(2,4-dichlorophenyl)-(R)-2-hydroxybutyl-(R)-1-carbamate(101)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-butanediol (Preparationexample 30) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.08 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m, 1H),1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d,J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.30˜7.50 (m, 3H)

Example 102 Synthesis of1-(2,6-dichlorophenyl)-(R)-2-hydroxybutyl-(R)-1-carbamate(102)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-butanediol (Preparationexample 42) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.09 g, yield10˜30%). ¹H NMR (400 MHz, CDCl₃) δ0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m,1H), 1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91(d, J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.25˜7.40 (m, 3H)

Example 103 Synthesis of1-(2,4-dichlorophenyl)-(R)-2-hydroxy-3-methyl-butyl-(R)-1-carbamate(103)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-3-methyl-(R,R)-1,2-propanediol(Preparation example 33) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), toobtain the title compound (0.01 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42(br s, 2H), 7.30˜7.50 (m, 3H)

Example 104 Synthesis of1-(2,6-dichlorophenyl)-(R)-2-hydroxy-3-methyl-butyl-(R)-1-carbamate(104)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-3-methyl-(R,R)-1,2-propanediol(Preparation example 45) was used instead of1-(2-chlorophenyl)-(S,S)-1,2-propanediol (Preparation example 14), toobtain the title compound (0.01 g, yield 10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42(br s, 2H), 7.25˜7.40 (m, 3H)

Example 105 Synthesis of1-(2,4-dichlorophenyl)-(R)-2-hydroxyhexyl-(R)-1-carbamate(105)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-(R,R)-1,2-hexanediol (Preparationexample 36) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.21 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.85 (t, J=7.2 Hz, 3H), 1.18˜1.33 (m, 4H),1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (brs, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 106 Synthesis of1-(2,6-dichlorophenyl)-(R)-2-hydroxyhexyl-(R)-1-carbamate(106)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-(R,R)-1,2-hexanediol (Preparationexample 48) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.12 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.85 (t, J=7.2 Hz, 3H), 1.18˜1.33 (m, 4H),1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (brs, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.16˜7.34 (m, 3H)

Example 107 Synthesis of1-(2,4-dichlorophenyl)-2-hydroxypropyl-1-carbamate(107)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-1,2-propanediol (Preparation example28) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.05 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H),4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.30˜7.50(m, 3H)

Example 108 Synthesis of1-(2,6-dichlorophenyl)-2-hydroxypropyl-1-carbamate(108)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-1,2-propanediol (Preparation example40) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.06 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.13 (d, J=6.8 Hz, 3H), 2.49 (d, J=4.0 Hz, 1H),4.66˜4.74 (m, 1H), 4.76 (br s, 2H), 6.20 (d, J=8.8 Hz, 1H), 7.25˜7.40(m, 3H)

Example 109 Synthesis of1-(2,3-dichlorophenyl)-(R)-2-hydroxypropyl-(R)-1-carbamate(109)

The substantially same method as described in Example 68 was conducted,except that 1-(2,3-dichlorophenyl)-1,2-propanediol (Preparation example59) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.02 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.15 (d, J=6.4 Hz, 3H), 3.66 (d, J=9.2 Hz, 1H),4.73 (br s, 2H), 5.43 (t, J=9.0 Hz, 1H), 5.62˜5.69 (m, 1H), 7.18˜7.22(m, 3H),

Example 110 Synthesis of1-(2,4-dichlorophenyl)-2-hydroxybutyl-1-carbamate(110)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-1,2-butanediol (Preparation example31) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.07 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m, 1H),1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d,J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.30˜7.50 (m, 3H)

Example 111 Synthesis of1-(2,6-dichlorophenyl)-2-hydroxybutyl-1-carbamate(111)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-1,2-butanediol (Preparation example43) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.10 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.77 (t, J=7.4 Hz, 3H), 0.92˜1.01 (m, 1H),1.18˜1.28 (m, 1H), 4.06˜4.13 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d,J=8.8 Hz, 1H), 6.4 (br s, 2H), 7.25˜7.40 (m, 3H)

Example 112 Synthesis of1-(2,4-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate(112)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-3-methyl-1,2-propanediol (Preparationexample 34) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.04 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42(br s, 2H), 7.30˜7.50 (m, 3H)

Example 113 Synthesis of1-(2,6-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate(113)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-3-methyl-1,2-propanediol (Preparationexample 46) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.01 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ1.00 (t, J=7.2 Hz, 6H), 1.73˜1.79 (m, 1H),3.67˜3.69 (m, 1H), 4.96 (d, J=6.0 Hz, 1H), 5.91 (d, J=8.8 Hz, 1H), 6.42(br s, 2H), 7.25˜7.40 (m, 3H)

Example 114 Synthesis of1-(2,4-dichlorophenyl)-2-hydroxyhexyl-1-carbamate(114)

The substantially same method as described in Example 68 was conducted,except that 1-(2,4-dichlorophenyl)-1,2-hexanediol (Preparation example37) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.21 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.85 (t, J=7.2 Hz, 3H), 1.18˜1.33 (m, 4H),1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (brs, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.30˜7.50 (m, 3H)

Example 115 Synthesis of1-(2,6-dichlorophenyl)-2-hydroxyhexyl-1-carbamate(115)

The substantially same method as described in Example 68 was conducted,except that 1-(2,6-dichlorophenyl)-1,2-hexanediol (Preparation example49) was used instead of 1-(2-chlorophenyl)-(S,S)-1,2-propanediol(Preparation example 14), to obtain the title compound (0.12 g, yield10˜30%).

¹H NMR (400 MHz, CDCl₃) δ0.85 (t, J=7.2 Hz, 3H), 1.18˜1.33 (m, 4H),1.48˜1.55 (m, 2H), 2.35 (d, J=4.4 Hz, 1H), 4.45˜4.50 (m, 1H), 4.76 (brs, 2H), 6.21 (d, J=8.4 Hz, 1H), 7.16˜7.34 (m, 3H)

Compounds 1 to 115 produced in Examples 1 to 115 were summarized infollowing Tables 1 and 2.

TABLE 1 Compounds 1 to 67 having the structure of Chemical Formula 1where ‘A’ is a carbamoyl derivative and ‘B’ is H A A = carbamoyl nderivative B No. X (position) 1^(st) Chiral 2^(nd) Chiral R¹ R² = B = H1 Cl 1(2-) S S Me H H 2 Cl 1(2-) R R Me H H 3 Cl 1(2-) Rac. Rac. Me H H4 Cl 1(2-) S R Me H H 5 Cl 1(2-) R S Me H H 6 Cl 1(2-) S S Et H H 7 Cl1(2-) R R Et H H 8 Cl 1(2-) Rac. Rac. Et H H 9 Cl 1(2-) S S Isopropyl HH 10 Cl 1(2-) R R Isopropyl H H 11 Cl 1(2-) Rac. Rac. Isopropyl H H 12Cl 1(2-) S S butyl H H 13 Cl 1(2-) R R butyl H H 14 Cl 1(2-) Rac. Rac.butyl H H 15 Cl 1(2-) S S Me Me H 16 Cl 1(2-) S S Me Propyl H 17 Cl1(2-) S S Me Isopropyl H 18 Cl 1(2-) S S Me Cyclopropyl H 19 Cl 1(2-) SS Me Cyclohexyl H 20 Cl 1(2-) S S Me Benzyl H 21 Cl 1(2-) S S MeBicyclo[2.2.1]heptane H 22 Cl 1(2-) R R Me Me H 23 Cl 1(2-) R R MePropyl H 24 Cl 1(2-) R R Me Isopropyl H 25 Cl 1(2-) R R Me Cyclopropyl H26 Cl 1(2-) R R Me Cyclohexyl H 27 Cl 1(2-) R R Me Benzyl H 28 Cl 1(2-)R R Me Bicyclo[2.2.1]heptane H 29 Cl 1(2-) Rac. Rac. Me Me H 30 Cl 1(2-)Rac. Rac. Me Propyl H 31 Cl 1(2-) Rac. Rac. Me Isopropyl H 32 Cl 1(2-)Rac. Rac. Me Cyclopropyl H 33 Cl 1(2-) Rac. Rac. Me Cyclohexyl H 34 Cl1(2-) Rac. Rac. Me Benzyl H 35 Cl 1(2-) Rac, Rac. MeBicyclo[2.2.1]heptane H 36 Cl 2(2,4-) S S Me H H 37 Cl 2(2,6-) S S Me HH 38 Cl 2(2,3-) S S Me H H 39 Cl 2(2,4-) S S Et H H 40 Cl 2(2,6-) S S EtH H 41 Cl 2(2,4-) S S Isopropyl H H 42 Cl 2(2,6-) S S Isopropyl H H 43Cl 2(2,4-) S S butyl H H 44 Cl 2(2,6-) S S butyl H H 45 Cl 2(2,4-) R RMe H H 46 Cl 2(2,6-) R R Me H H 47 Cl 2(2,3-) R R Me H H 48 Cl 2(2,4-) RR Et H H 49 Cl 2(2,6-) R R Et H H 50 Cl 2(2,4-) R R Isopropyl H H 51 Cl2(2,6-) R R Isopropyl H H 52 Cl 2(2,4-) R R butyl H H 53 Cl 2(2,6-) R Rbutyl H H 54 Cl 2(2,4-) Rac, Rac. Me H H 55 Cl 2(2,6-) Rac, Rac. Me H H56 Cl 2(2,3-) Rac, Rac. Me H H 57 Cl 2(2,4-) Rac, Rac. Et H H 58 Cl2(2,6-) Rac, Rac. Et H H 59 Cl 2(2,4-) Rac, Rac. Isopropyl H H 60 Cl2(2,6-) Rac, Rac. Isopropyl H H 61 Cl 2(2,4-) Rac, Rac. butyl H H 62 Cl2(2,6-) Rac, Rac. butyl H H 63 F 1(2-) S S Me H H 64 F 1(2-) R R Me H H65 I 1(2-) S S Me H H 66 I 1(2-) R R Me H H 67 I 1(2-) S S Et H H

TABLE 2 Compounds 68 to 115 having the structure of Chemical Formula 1where ‘A’ is H and ‘B’ is a carbamoyl derivative B B = n A carbamoyl(po- 1^(st) 2^(nd) A = derivative No. X sition) Chiral Chiral R¹ H R³=68 Cl 1(2-) S S Me H H 69 Cl 1(2-) R R Me H H 70 Cl 1(2-) Rac. Rac. Me HH 71 Cl 1(2-) S S Me H Me 72 Cl 1(2-) R R Me H Me 73 Cl 1(2-) Rac. Rac.Me H Me 74 Cl 1(2-) S S Me H Propyl 75 Cl 1(2-) R R Me H Propyl 76 Cl1(2-) Rac. Rac. Me H Propyl 77 Cl 1(2-) S S Me H Isopropyl 78 Cl 1(2-) RR Me H Isopropyl 79 Cl 1(2-) Rac. Rac. Me H Isopropyl 80 Cl 1(2-) S S MeH Cyclopropyl 81 Cl 1(2-) R R Me H Cyclopropyl 82 Cl 1(2-) Rac. Rac. MeH Cyclopropyl 83 Cl 1(2-) S S Me H Cyclohexyl 84 Cl 1(2-) R R Me HCyclohexyl 85 Cl 1(2-) Rac. Rac. Me H Cyclohexyl 86 Cl 1(2-) S S Me HBenzyl 87 Cl 1(2-) R R Me H Benzyl 88 Cl 1(2-) Rac. Rac. Me H Benzyl 89Cl 2(2,4-) S S Me H H 90 Cl 2(2,6-) S S Me H H 91 Cl 2(2,3-) S S Me H H92 Cl 2(2,4-) S S Et H H 93 Cl 2(2,6-) S S Et H H 94 Cl 2(2,4-) S SIsopropyl H H 95 Cl 2(2,6-) S S Isopropyl H H 96 Cl 2(2,4-) S S Butyl HH 97 Cl 2(2,6-) S S Butyl H H 98 Cl 2(2,4-) R R Me H H 99 Cl 2(2,6-) R RMe H H 100 Cl 2(2,3-) R R Me H H 101 Cl 2(2,4-) R R Et H H 102 Cl2(2,6-) R R Et H H 103 Cl 2(2,4-) R R Isopropyl H H 104 Cl 2(2,6-) R RIsopropyl H H 105 Cl 2(2,4-) R R Butyl H H 106 Cl 2(2,6-) R R Butyl H H107 Cl 2(2,4-) Rac. Rac. Me H H 108 Cl 2(2,6-) Rac. Rac. Me H H 109 Cl2(2,3-) Rac. Rac. Me H H 110 Cl 2(2,4-) Rac. Rac. Et H H 111 Cl 2(2,6-)Rac. Rac. Et H H 112 Cl 2(2,4-) Rac. Rac. Isopropyl H H 113 Cl 2(2,6-)Rac. Rac. Isopropyl H H 114 Cl 2(2,4-) Rac. Rac. Butyl H H 115 Cl2(2,6-) Rac. Rac. Butyl H H

Biological Experimental Example 1 Measurement of Anti-Epilepsy Activity

In the MES test (Ref., G. Villetti et al. Neuropharmacology 40 (2001)866-878), an electrical stimulus (mice; 50 mA, 60 Hz, 0.2 sec and rats;150 mA 60 Hz, 0.2 sec in the test animal) supplied by 11A Shocker (IITCLife Science Company) was delivered through corneal electrodes. All miceor rats assigned to any electroshock at peak time were treated with eachtest compound sample which was dissolved in 30% PEG400 prepared bysaline solvent applied to oral before the test. If the test animalstretching their hind limb in a straight line weren't observed in theMES test, the results indicate that the test sample had an anti-epilepsyactivity. Three doses of the test sample were administered orally toover 18 mice (6 mice per dose) for evaluating the respective doses atwhich 50% of the animals are protected from seizure (ED50). The value ofED50 (median effective dose) is calculated by Litchfield and Wicoxonlog-probit method which is a dose-response relationship. Then, the testresults are shown in following Table 3. Experimental animal, male ICRmice and male SD rats, were purchased from OrientBio or Nara biotech,Korea, and housed 4-5 mice per a cage for 4-5 days. The range of micebody weight was used between 19 and 26 grams and range of rats bodyweight was used between 100 and 130 grams.

Biological Experimental Example II Measurement of Anti-Epilepsy ActivityThrough scPTZ

In this experiment, each test compound sample was formulated asdescribed in Biological Experimental Example I, and administeredintraperitoneally to test animals (mice; ICR or Rat; SD); Experimentalanimal, male ICR mice and male SD rats, were purchased from OrientBio orNara biotech, Korea, and housed 4-5 mice per a cage for 4-5 days. Therange of mice body weight was used between 19 and 26 grams and range ofrats body weight was used between 100 and 130 grams. After Peak time(0.5, 1, 2 and 4 hr) from the administration, PTZ(Pentylenetetrazol) wasadministered subcutaneously in the concentration capable of inducing 97%intermittent convulsions (mice: 100˜110 mg/kg·bw, 100 ul/g, or rats:90˜110 mg/kg·bw, 20 ul/g). If clonic seizure was not observed for atleast 3 seconds in the PTZ administered animal, it can be consideredthat the test compound has anti-epilepsy activity. The median effectivedose (ED50) is determined using 6 animals per a concentration (totalthree different concentrations), and calculated by Litchfield andWicoxon log-probit method which is a dose-response relationship. Theobtained results are shown in following Table 3.

Biological Experimental Example III Measurement of Neurotoxicity

The measurement of neurotoxicity of the test compounds was conducted bythe method of Dunham and Miya [Dunham, N. W. and Miya, T. S. 1957. Anote on a simple apparatus for detecting neurological deficit in ratsand mice. J. Am. Pharm. Assoc. (Baltimore) 46: 208-209]. In the method,motor abilities of the test animals can be determined by observingwhether the test animals can walk without falling from a rotator,thereby determining the value of neurotoxicity of each compound. Term“TD50” means the respective dose of the test compound at which 50% ofthe test animal exhibit neurotoxicity. They were pre-trained on therotarod (Rotarod; Columbus instrument, rota-max, USA) at 6 rpm for 5 min24 hr prior to the test. The peak time was determined by administrationtest material's random dose for 0.5, 1, 2, 4 hour. To evaluate theminimal neurotoxicity of the compound, the mice were placed on theRotarod (rod circle; 3 Cm) at 6 rpm and the test animal fails tomaintain walking once or more during 1 minute, it can be regarded thatthe test animal exhibits neurotoxicity. The ratio of TD50 to ED50(TD50/ED50) is called as a protective index, and useful as a parameterfor comparison of pharmaceutical efficacy and neurotoxicity. Theobtained results are shown in following Table 3.

[Statistical Analysis]

The obtained results are shown as mean±sem. The difference between thegroups was statistically analyzed by ANOVA, and then, further examinedby Dunnett's test or Bonferroni test. If p is less than 0.05, it wasdetermined that the difference between the groups had statisticalsignificance.

TABLE 3 Measurement results of anti-epilepsy activity of compounds inthe test animals (Mice and Rats) MES test(po) ScPTZ test(ip) Peak PeakTD50 PI (TD50/ Compound ED50 Time ED50 Time (mg/kg ED50 in No. (mg/kg)(h) (mg/kg) (h) po) MES) 1 13.0 2 15.8 2 218.1 16.8 2 51.0 0.25 38.8 0.5372.0 7.3 3 31.4 2 15.3 0.5 378.3 12.0 4 82.4 0.5 5 84.1 0.5 15.0 0.5275.2 3.3 6 22.2 1 17.9 0.5 8  100^(a)(100%) 9 67.1 0.5 12 100^(a)(75%)13 200^(a)(75%) 14  200^(a)(100%) 15 100^(a)(75%) 16 200^(a)(25%) 18 200^(a)(100%) 23 200^(a)(25%) 25 200^(a)(25%) 29 200^(a)(75%) 30200^(a)(25%) 31 200^(a)(25%) 32 200^(a)(100%) 36 82.8 37 25.8 0.25 25.70.25 131.6 5.1 38 91.4 2 39 41.2 1 24.3 0.5 40 46.9 42 35.2 0.5 43100^(a)(25%) 44 100^(a)(75%) 45 200^(a)(0%)  46 35.2 1 63  50^(a)(100%)65  50^(a)(100%) 67  100^(a)(100%) # a: Injection amount(mg/kg),Protection % (4 mice); b: Injection amount(mg/kg), Protection % (6Rats);

Biological Experimental Example IV Measurement of PharmaceuticalEfficacy Duration Time Through MES

The ED50 values according to time were measured in the test animals(mice and rats) after oral administration of test compound 1 asdescribed in Biological Experimental Example I. The obtained results areshown in following Table 4 and FIG. 1.

TABLE 4 Duration of MES test ED50 (mg/kg), (po) Time No species 0.25 h0.5 h 1 h 2 h 3 h 4 h 6 h 8 h 12 h 1 Mouse 21.2 22.5 13.3 13.0 14.7 18.730.0 49.4 118.8 Rat — 5.9 3.3 1.4 — 6.9 — 14.4 36.1

As shown in Table 4 and FIG. 1, the test compound 1 exhibits theefficacy duration time of at least 12 hours in both of the tested ratsand mice.

Biological Experimental Example V Measurement of Pharmaceutical EfficacyDuration Time Through scPTZ

The ED50 values according to time were measured in the test animals(mice and rats) after intraperitoneal administration of test compound 1as described in Biological Experimental Example II. The obtained resultsare shown in following Table 5 and FIG. 2.

TABLE 5 Duration of scPTZ test ED50 (mg/kg), (ip) Time No species 0.5 h1 h 2 h 4 h 6 h 8 h 12 h 1 Mouse 17.3 16.9 15.8 27.4 52.2 80.7 201.1 Rat18.9 14.5 21.0 31.0 — 41.3 76.7

As shown in Table 5 and FIG. 2, the test compound 1 exhibits theefficacy duration time of at least 12 hours in both of the tested ratsand mice.

As the pharmaceutical efficacy duration time of a drug is longer, theadministration number of the drug becomes decreased, thereby increasingthe administration convenience of a patient. Such advantages may beparticularly preferable for a patient suffered from a disease thatrequires long term administration of a drug, such as epilepsy. Inaddition, the decrease of the administration number may be profitable ineconomic aspect and helpful to increase the quality of life of thepatient.

What is claimed is:
 1. A method of preventing or treating epilepsycomprising administering a pharmaceutically effective amount of a phenylcarbamate compound represented by Chemical Formula 1 or apharmaceutically acceptable salt thereof, to a subject in need ofpreventing or treating epilepsy:

wherein X is a halogen; n is an integer from 1 to 5; R1 is a linear orbranched alkyl group of C1-C4; A is hydrogen or a carbamoyl derivativerepresented by

B is hydrogen, a carbamoyl derivative represented by

trialkyl silyl groups, trialkylaryl silyl groups (wherein the totalnumber of alkyl and aryl groups is three), or a trialkyl silyl ethergroup, wherein each alkyl group is independently selected from the groupconsisting of linear, branched, or cyclic C1-C4 alkyl groups, and eacharyl group is independently selected from the group consisting of C5-C8aryl groups; A and B are not carbamoyl derivatives at same time; and R2and R3 may be the same as or different from each other, andindependently selected from the group consisting of hydrogen, a linearor branched alkyl group of C1-C4, a cycloalkyl group of C3-C8, andbenzyl group.
 2. The method according to claim 1, wherein X is chlorine,fluorine, iodine, or bromine; n is 1 or 2; R1 is methyl group, ethylgroup, isopropyl group, or butyl group; A is hydrogen or a carbamoylderivative represented by

B is hydrogen, a carbamoyl derivative represented by

a trimethyl silyl (TMS) group, a triethyl silyl (TES) group, atriisopropyl silyl (TIPS) group, t-butyl dimethyl silyl (TBDMS) group, at-butyl diphenyl silyl (TBDPS) group, or a trialkyl silyl ether group,wherein each alkyl group is independently selected from the groupconsisting of linear, branched, or cyclic C1-C4 alkyl groups; A and Bare not carbamoyl derivatives at same time; and R2 and R3 are the sameas or different from each other, and independently selected from thegroup consisting of hydrogen, methyl group, propyl group, isopropylgroup, cyclopropyl group, cyclohexyl group, bicycloheptane group, andbenzyl group.
 3. The method according to claim 1, wherein the compoundis selected from the group consisting of:1-(2-chlorophenyl)-1-hydroxypropyl-2-carbamate,1-(2-chlorophenyl)-1-hydroxybutyl-2-carbamate,1-(2-chlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate,1-(2-chlorophenyl)-1-hydroxyhexyl-2-carbamate,1-(2-chlorophenyl)-1-hydroxypropyl-2-N-methylcarbamate,1-(2-chlorophenyl)-1-hydroxypropyl-2-N-propylcarbamate,1-(2-chlorophenyl)-1-hydroxypropyl-2-N-isopropylcarbamate,1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclopropylcarbamate,1-(2-chlorophenyl)-1-hydroxypropyl-2-N-cyclohexylcarbamate,1-(2-chlorophenyl)-1-hydroxypropyl-2-N-benzylcarbamate,1-(2-chlorophenyl)-1-hydroxypropyl-2-N-bicyclo[2,2,1]heptanecarbamate,1-(2,4-dichlorophenyl)-1-hydroxypropyl-2-carbamate,1-(2,6-dichlorophenyl)-1-hydroxypropyl-2-carbamate,1-(2,4-dichlorophenyl)-1-hydroxybutyl-2-carbamate,1-(2,6-dichlorophenyl)-1-hydroxybutyl-2-carbamate,1-(2,4-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate,1-(2,6-dichlorophenyl)-1-hydroxy-3-methyl-butyl-2-carbamate,1-(2,4-dichlorophenyl)-1-hydroxyhexyl-2-carbamate,1-(2,6-dichlorophenyl)-1-hydroxyhexyl-2-carbamate,1-(2-chlorophenyl)-2-hydroxypropyl-1-carbamate,1-(2-chlorophenyl)-2-hydroxypropyl-1-N-methylcarbamate,1-(2-chlorophenyl)-2-hydroxypropyl-1-N-propylcarbamate,1-(2-chlorophenyl)-2-hydroxypropyl-1-N-isopropylcarbamate,1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclopropylcarbamate,1-(2-chlorophenyl)-2-hydroxypropyl-1-N-cyclohexylcarbamate,1-(2-chlorophenyl)-2-hydroxypropyl-1-N-benzylcarbamate,1-(2,4-dichlorophenyl)-2-hydroxypropyl-1-carbamate,1-(2,6-dichlorophenyl)-2-hydroxypropyl-1-carbamate,1-(2,4-dichlorophenyl)-2-hydroxybutyl-1-carbamate,1-(2,6-dichlorophenyl)-2-hydroxybutyl-1-carbamate,1-(2,4-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate,1-(2,6-dichlorophenyl)-2-hydroxy-3-methyl-butyl-1-carbamate,1-(2,4-dichlorophenyl)-2-hydroxyhexyl-1-carbamate,1-(2,6-dichlorophenyl)-2-hydroxyhexyl-1-carbamate,1-(2-fluorophenyl)-1-hydroxypropyl-2-carbamate,1-(2-iodophenyl)-1-hydroxypropyl-2-carbamate,1-(2-iodophenyl)-1-hydroxybutyl-2-carbamate,1-(2,3-dichlorophenyl)-1-hydroxypropyl-2-carbamate, and1-(2,3-dichlorophenyl)-2-hydroxypropyl-1-carbamate.
 4. The methodaccording to claim 1, wherein the compound is in the form of racemate,enantiomer, diastereomer, a mixture of enantiomer, or a mixture ofdiastereomer.